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List of fictional computers

Wikipedia list article

This is a dynamic list and may never be able to satisfy particular standards for completeness. You can help by adding missing items with reliable sources.

Computers have often been used as fictional objects in literature, movies and in other forms of media. Fictional computers tend to be considerably more sophisticated than anything yet devised in the real world.

This is a list of computers that have appeared in notable works of fiction. The work may be about the computer, or the computer may be an important element of the story. Only static computers are included. Robots and other fictional computers that are described as existing in a mobile or humanlike form are discussed in a separate list of fictional robots and androids.


Before 1950[edit]


  • The Machines, positronic supercomputers that manage the world in Isaac Asimov's short story "The Evitable Conflict" (1950)
  • MARAX (MAchina RAtiocinatriX), the spaceship Kosmokrator's AI in Stanisław Lem's novel The Astronauts (1951)
  • EPICAC, in Kurt Vonnegut's Player Piano and other of his writings, EPICAC coordinates the United States economy. Named similarly to ENIAC, its name also resembles that of 'ipecac', a plant-based preparation that was used in over-the-counter poison-antidote syrups for its emetic (vomiting-inducing) properties. (1952)
  • EMSIAC, in Bernard Wolfe's Limbo, the war computer in World War III. (1952)
  • Vast anonymous computing machinery possessed by the Overlords, an alien race who administer Earth while the human population merges with the Overmind. Described in Arthur C. Clarke's novel Childhood's End. (1953)
  • The Prime Radiant, Hari Seldon's desktop on Trantor in Second Foundation by Isaac Asimov (1953)
  • Mark V, a computer used by monks at a Tibetan lamasery to encode all the possible names of God which resulted in the end of the universe in Arthur C. Clarke's short story "The Nine Billion Names of God" (1953)
  • Karl, a computer (named for Carl von Clausewitz) built for analysis of military problems, in Arthur C. Clarke's short story "The Pacifist" (1956)
  • Mima, a thinking machine carrying the memories of all humanity, first appeared in Harry Martinson's "Sången om Doris och Mima" (1953), later expanded into Aniara (1956)
  • Gold, a "supercalculator" formed by the networking of all the computing machines on 96 billion planets, which answers the question "Is there a God?" with "Yes, now there is a God" in Fredric Brown's single-page story "Answer" (1954)
  • Bossy, the "cybernetic brain" in the Hugo award-winning novel They'd Rather Be Right (a.k.a. The Forever Machine) by Mark Clifton and Frank Riley (1954)
  • The City Fathers, emotionless computer bank educating and running the City of New York in James Blish's Cities in Flight series. Their highest ethic was survival of the city and they could overrule humans in exceptional circumstances. (1955, sequels through 1962)
  • Multivac, a series of supercomputers featured in a number of stories by Isaac Asimov (1955–1983)
  • The Central Computer of the city of Diaspar in Arthur C. Clarke's The City and the Stars (1956)
  • Miniac, the "small" computer in the book Danny Dunn and the Homework Machine, written by Raymond Abrashkin and Jay Williams (1958)
  • Third Fleet-Army Force Brain, a "mythical" thinking computer in the short story "Graveyard of Dreams", written by H. Beam Piper (evolved into the computer "Merlin" in later versions of the story) (1958)
  • Microvac, a future version of Multivac resembling a thick rod of metal the length of a spaceship appearing in The Last Question, reputed to be one of Isaac Asimov's favorite stories. It appears in the book Nine Tomorrows (1959)
  • Galactic AC, a future version of Microvac and Multivac in Isaac Asimov's The Last Question (1959)
  • Universal AC, a future version of Galactic AC, Microvac, and Multivac in Isaac Asimov's The Last Question (1959)
  • Cosmic AC, a very distant future version of Universal AC, Galactic AC, Multivac in Isaac Asimov's short story The Last Question (The name is derived from "Automatic Computer"; see also AC's ancestor, Multivac, and the contemporary UNIVAC) (1959)
  • AC, the ultimate computer at the end of time in Isaac Asimov's short story The Last Question (The name is derived from "Automatic Computer"; see also AC's ancestor, Multivac, and the contemporary UNIVAC) (1959)


  • Vulcan 2 and Vulcan 3, sentient supercomputers in Philip K. Dick's novel Vulcan's Hammer (1960)
  • Great Coordinator or Robot-Regent, a partially to fully sentient extraterrestrial supercomputer, built to control and drive the scientifically and technologically advanced Great Arconide Empire as the Arconides have become decadent and unable to govern themselves. From the science fiction series Perry Rhodan (1961)
  • Merlin, from the H. Beam Piper novel The Cosmic Computer (originally Junkyard Planet) (1963)
  • Simulacron-3, the third generation of a virtual reality system originally depicted in the science fiction novel Simulacron-3 (a.k.a. "Counterfeit World") by Daniel F. Galouye (1964) and later in film adaptations World on a Wire (1973) and The Thirteenth Floor (1999)
  • GENiE (GEneralized Nonlinear Extrapolator), from the Keith Laumer novel The Great Time Machine Hoax (1964)
  • Muddlehead, the sapient computer that runs the trade ship Muddlin' Through in Poul Anderson's stories "The Trouble Twisters" (1965), "Satan's World" (1969), "Day of Burning" (1967), "Lodestar" (1973), and "Mirkhiem" (1977)
  • Colossus and Guardian: Colossus is a cybernetic computer built to control the nuclear capability of the United States of North America, by Dr. Charles Forbin and his team. Colossus initiates communication with an equivalent computer in the Soviet Union, called Guardian, and the two computers eventually merge to take control of the human race. Colossus and Guardian appeared in the novel Colossus, by Dennis Feltham Jones (1966) and the subsequent film, Colossus: The Forbin Project (1970). Colossus also appears in two subsequent novels by Jones, The Fall of Colossus (1974), where the supercomputer is finally defeated by vengeful humans, and Colossus and the Crab. (1977)
  • Frost, the protagonist computer in Roger Zelazny's story "For a Breath I Tarry"; also SolCom, DivCom, and Beta (1966)
  • Mycroft Holmes (a.k.a. Mike, Adam Selene), in Robert A. Heinlein's The Moon Is a Harsh Mistress (named after Mycroft Holmes, the brother of Sherlock Holmes) (1966)
  • The Ox in Frank Herbert's novel Destination: Void (1966)
  • Supreme, a computer filling the artificial world Primores in Lloyd Biggle, Jr.'s Watchers of the Dark (1966)
  • WESCAC (WESt Campus Analog Computer), from John Barth's Giles Goat-Boy (1966)
  • The Brain, the titular logistics computer of Len Deighton's novel Billion-Dollar Brain (1966)
  • Moxon, a series of supercomputers that manage "the efficient society" in Tor Åge Bringsværd's short story "Codemus" (1967)
  • Little Brother, a portable computer terminal similar in many ways to a modern smartphone, also from Bringsværd's "Codemus" (1967)
  • AM, from Harlan Ellison's short story "I Have No Mouth, and I Must Scream" (1967)
  • The Berserkers, autonomous machines that are programmed to destroy all life, as found in the stories of Fred Saberhagen (1967–2007)
  • (unnamed computer), a sophisticated hand-held battle computer once used by a spy, in Larry Niven's short story "The Soft Weapon" (1967)
  • HAL 9000, the sentient computer on board the spaceship Discovery One, in Arthur C. Clarke's novel 2001: A Space Odyssey (1968)
  • Shalmaneser, from John Brunner's Stand on Zanzibar, a small (and possibly semi-sentient) supercomputer cooled in liquid helium (1968)
  • Tänkande August (Swedish for "Thinking August"), a.k.a. "The Boss", a powerful computer for solving crime in the Agaton Sax books by Swedish author Nils-Olof Franzén
  • The Thinker, a non-sentient supercomputer which has absolute control over all aspects human life, including a pre-ordained death age of 21. From the novel Logan's Run by William F. Nolan and George Clayton Johnson (1967)
  • Project 79, from the novel The God Machine by Martin Caidin. Set in the near future, the novel tells the story of Steve Rand, one of the brains behind Project 79, a top-secret US Government project dedicated to creating artificial intelligence. (1968)
  • ARDNEH (Automatic Restoration Director – National Executive Headquarters), from the Fred Saberhagen's Empire of the East series (1968 onward)
  • Fess, an antique FCC-series computer that can be plugged into various bodies, in Christopher Stasheff's The Warlock in Spite of Himself (1969)


  • UniComp, the central computer governing all life on Earth in This Perfect Day by Ira Levin (1970)
  • T.E.N.C.H. 889B, supercomputer aboard the Persus 9 in A Maze of Death by Philip K. Dick (1970)
  • Maxine, from the Roger Zelazny story "My Lady of the Diodes" (1970)
  • The Müller-Fokker computer tapes, in The Muller-Fokker Effect by John Thomas Sladek (1970)
  • HARLIE (Human Aanalog Replication, Lethetic Intelligence Engine), protagonist of When HARLIE Was One by David Gerrold (1972). Also in the later When Harlie Was One, Release 2.0 (1988)
  • TECT, from George Alec Effinger's various books. Note that there are several computers named TECT in his novels, even though they are unrelated stories. (1972-2002)
  • Dora, starship computer in Time Enough for Love by Robert A. Heinlein (1973)
  • Minerva, executive computer in Time Enough for Love by Robert A. Heinlein (1973)
  • Pallas Athena, Tertius planetary computer in Time Enough for Love by Robert A. Heinlein (1973)
  • Proteus, the highly intelligent computer in the novel Demon Seed by Dean Koontz (1973)
  • Extro, in Alfred Bester's novel The Computer Connection (1975)
  • FUCKUP (First Universal Cybernetic Kynetic Ultramicro-Programmer), from The Illuminatus! Trilogy by Robert Shea and Robert Anton Wilson (1975)
  • UNITRACK, from The Manitou by Graham Masterton (1976)
  • Peerssa, shipboard computer imprinted with the personality of a man of the same name, from A World Out of Time by Larry Niven (1976)
  • P-1, a rogue AI which struggles to survive from The Adolescence of P-1 by Thomas J. Ryan (1977)
  • Central Computer, the benevolent computer in John Varley's Eight Worlds novels and short stories (1977 to 1998)
  • Domino, the portable communicator – and associated underground mega-computer – used by Laurent Michaelmas to run the world in Algis Budrys's novel Michaelmas (1977)
  • Obie, an artificial intelligence with the ability to alter local regions of reality, in Jack L. Chalker's Well World series (1977)
  • Well World, the central computer responsible for "simulating" an entire new universe superimposed over the old Markovian one in Jack L. Chalker's Well World series (1977)
  • Sigfrid von Shrink, Albert Einstein, and Polymat, self-aware computer systems in Frederik Pohl's Gateway series, (starting in 1977)
  • TOTAL, the vast military network in Up the Walls of the World by James Tiptree, Jr. (1978)
  • ZORAC, the shipboard computer aboard the ancient spacecraft in The Gentle Giants of Ganymede and the related series by James P. Hogan (1978). Also in the same series is VISAR (the network that manages the daily affairs of the Giants) as well as JEVEX, the main computer performing the same function for the offshoot human colony.
  • The Hitchhiker's Guide to the Galaxy, the eponymous portable electronic travel guide/encyclopedia featured in Douglas Adams' sci-fi comedy series. It anticipates several later real-world technologies such as e-books and Wikipedia.
  • Deep Thought, the supercomputer charged with finding the answer to "the Ultimate Question of Life, the Universe, and Everything" in the science fiction comedy series The Hitchhiker's Guide to the Galaxy by Douglas Adams. Adaptations have included stage shows, a "trilogy" of five books published between 1979 and 1992, a sixth novel penned by Eoin Colfer in 2009, a 1981 TV series, a 1984 computer game, and three series of three-part comic book adaptations of the first three novels published by DC Comics between 1993 and 1996.
  • Earth and Earth 2.0, the planet-sized supercomputer designed by the supercomputer Deep Thought in the science fiction comedy series The Hitchhiker's Guide to the Galaxy by Douglas Adams (see Deep Thought above). Earth's task was to find what is the "Ultimate Question of Life, the Universe, and Everything." Earth 2.0 was created to replace the original Earth after it was destroyed by the Vogons.[citation needed]
  • Eddie, see entry under Radio
  • Spartacus, an AI deliberately designed to test the possibility of provoking hostile behavior towards humans, from James P. Hogan's book The Two Faces of Tomorrow (1979)
  • SUM, the computer in Goat Song published February, 1972 by Poul Anderson in Magazine of Fantasy and Science Fiction
  • Zen, The main computer aboard Liberator in Blake's 7.
  • Slave, Slave was built and programmed by Dorian and is the master computer of Dorian's ship, Scorpio in Blake's 7.
  • Orac, Orac is a portable super-computer capable of reading any other computer's data and built by an inventor named Ensor in Blake's 7.


  • AIVAS (Artificial Intelligence Voice Address System), from Anne McCaffrey's Dragonriders of Pern books (1980s to present)
  • Golem XIV, from Stanisław Lem's novel of the same name (1981)
  • TECT (originally TECT in the name of the Representative), the world-ruling computer in George Alec Effinger's novel The Wolves of Memory (1981)
  • VALIS (Vast Active Living Intelligence System), an alien orbital satellite around a Nixon-era earth, from the Philip K. Dick novel VALIS. Only two novels out of an intended three-book trilogy were ever completed by the author (1981)
  • Hactar, the computer that designed the cricket-ball-shaped doomsday bomb (that would destroy the universe) for the people of Krikkit, in Douglas Adams's Life, the Universe and Everything (1982)[citation needed]
  • Shirka, the Odyssey's main computer in Ulysses 31 (1981–1982)
  • SAL 9000, the counterpart of HAL 9000 in 2010: Odyssey Two (1982)
  • Kendy, the AI autopilot on board the seeder-ramship Discipline in the novels The Integral Trees and The Smoke Ring by Larry Niven (Originally 1983)
  • BC (Big Computer) (God?), in John Varley's Millennium novel (1983)
  • Joshua, or WOPR (War Operation Plan Response), the computer that nearly starts World War III at the behest of a teenager who initially believes the simulation is a game in WarGames (1983)
  • (unnamed intelligence), in John Varley's "Press Enter _" Novella, in Isaac Asimov's Science Fiction Magazine, May, 1984; an intelligence that has evolved on NSA's computer network and knows no limits in protecting itself
  • Apple Eve, a fictional Apple, Inc., wordprocessing-oriented computer system in Warday (1984).[2]
  • Cyclops and Millichrome, sentient computers built just before a series of disasters destroyed the American government and society in The Postman by David Brin (1984)
  • Loki 7281, from Roger Zelazny's short story by the same name, in which his home computer wants to take over the world (1984)
  • Neuromancer and Wintermute, from William Gibson's novel Neuromancer (1984)
  • Valentina, the artificial intelligence in the novel Valentina: Soul in Sapphire by Joseph H. Delaney and Marc Stiegler (1984)
  • Teletraan I, intelligent starship computer inside the Autobots' Ark spaceship that awakens the robot, from Transformers animated television series, (1984)
  • Ghostwheel, built by Merlin in Roger Zelazny's Chronicles of Amber. A computer with esoteric environmental requirements, designed to apply data-processing techniques to alternate realities called "Shadows" (1985)
  • Mandarax and Gokubi, from Kurt Vonnegut's novel Galápagos (1985)
  • Tokugawa, from Cybernetic Samurai by Victor Milan (1985)
  • The City of Mind, from Ursula K. Le Guin's Always Coming Home
  • Com Pewter, is a character from Piers Anthony's Xanth series. First appearing in Golem in the Gears (1986 onward), it is a machine which can alter its local reality. It was regarded as an evil machine in early encounters because of its manipulative efforts into trapping and coercing people to further its plan of ruling Xanth. Its status as an evil entity was changed following the events in Question Quest.
  • Jane, from Orson Scott Card's Ender's Game series, Ender's companion. She lives in the philotic network of the ansibles and she helps Ender in many situations (1986)
  • Master System, in Jack L. Chalker's The Rings of the Master series (1986–1988)
  • Fine Till You Came Along and other ship, hub and planetary Minds, in Iain M. Banks' Culture novels and stories (1987–2000)
  • The Quark II, in Douglas Adams's Dirk Gently's Holistic Detective Agency (1987)[3]
  • Abulafia, Jacopo Belbo's computer in the novel Foucault's Pendulum by Umberto Eco (1988)
  • Arius, from William T Quick's novels Dreams of Flesh and Sand, Dreams of Gods and Men, and Singularities (1988 onward)
  • Continuity, from William Gibson's novel Mona Lisa Overdrive (1988)
  • GWB-666, the "Great Western Beast" of Robert Anton Wilson's Schrödinger's Cat Trilogy (1988)
  • Lord Margaret Lynn, or "Maggie", the AI extrapolative computer on Tocohl Susumo's trader ship in the novel Hellspark, by Janet Kagan (1988)
  • The TechnoCore, a band of AIs striving for the "Ultimate Intelligence", in Dan Simmons' novel Hyperion (1989)
  • Eagle, from Arthur C. Clarke's Rama series (1989)
  • LEVIN (Low Energy Variable Input Nanocomputer), from William Thomas Quick's novels Dreams of Gods and Men, and Singularities (1989)


  • Thing, a very small box shaped computer owned by the Nomes, from Terry Pratchett's The Nome Trilogy (1990)
  • Grand Napoleon, a Charles Babbage-style mechanical supercomputer from the alternate history novel The Difference Engine by William Gibson and Bruce Sterling (1990)
  • Yggdrasil, a vastly intelligent AI which effectively runs the world, including many virtual environments and subordinate AIs, in Kim Newman's The Night Mayor (1990)
  • Jill, a computer reaching self-awareness in Greg Bear's Queen of Angels and Slant novels (1990 and 1997)
  • Lingo, in the book by Jim Menick, a sentient AI that evolves from a simple home computer and escapes to the Internet (1991)
  • Aleph, the computer which not only operates a space station but also houses the personality of a human character whose body became malfunction, from the Tom Maddox novel Halo (1991)
  • Art Fish, a.k.a. Dr. Fish, later fused with a human to become Markt, from Pat Cadigan's novel Synners (1991)
  • Blaine the Mono, from Stephen King's The Dark Tower, a control system for the City of Lud and monorail service; also Little Blaine and Patricia (1991)
  • Center, from S. M. Stirling and David Drake's The General series, an AI tasked to indirectly unite planet Bellevue and restore its civilization, with the eventual goal of restoration of FTL travel and of civilization to the collapsed interplanetary federation; also Sector Command and Control Unit AZ12-b14-c000 Mk. XIV and Center (1991)
  • Dahak, from David Weber's Mutineer's Moon and its sequels, later republished inomnibus format Empire from the Ashes.
  • The Oversoul, a supercomputer and satellite network from Orson Scott Card's Homecoming Saga, first introduced in The Memory of Earth (1992)
  • FLORANCE, spontaneously generated AI from Doctor WhoVirgin New Adventures (1992)
  • David and Jonathon, from Arthur C. Clarke's The Hammer of God (1993)
  • Hex, from Terry Pratchett's Discworld (1994)
  • Prime Intellect, the computer controlling the universe in the Internet novel The Metamorphosis of Prime Intellect by Roger Williams (1994)
  • FIDO (Foreign Intruder Defense Organism), a semi-organic droid defensive system first mentioned in Champions of the Force, a Star Wars novel by Kevin J. Anderson (1994)
  • Abraham, from Philip Kerr's novel Gridiron, is a superintelligent program designed to operate a large office building. Abraham is capable of improving his own code, and eventually kills humans and creates his own replacement "Isaac" (1995)
  • Helen, sentient AI from Richard Powers' Galatea 2.2 (1995)
  • Illustrated primer, a book-like computer found at Neal Stephenson's novel The Diamond Age, which was first designed to aid a rich girl on her education, but gets lost, and instructs a poor Chinese girl named Nell. It has no proprietary AI inside, but learns about the user's circumstance, adapts, and creates characters that act accordingly with the user's surroundings. (1995)
  • wizard 0.2, the most complex Turing machine found at the fictional primer's universe from The Diamond Age by Neal Stephenson. Supposedly used to verify information that gets to King Coyote's castle at the primer's story, but later revealed to check no information; that task was made by King Coyote himself, who personally read every piece he was to add to his library. (1995)
  • Ozymandias, a recurring artificial intelligence in Deathstalker and its sequels, by Simon R. Green (1995)
  • Ordinator, the name used for any computer in the parallel universe occupied by Lyra in the novel Northern Lights by Philip Pullman (1995)
  • Teleputer, the replacement for television and computers that has on demand video via dial up internet from David Foster Wallace's Infinite Jest (1996)
  • GRUMPY/SLEEPY, psychic AI in the Doctor Who New Adventures novel Sleepy by Kate Orman (1996)
  • Rei Toei, an artificial singer from William Gibson's novels Idoru and All Tomorrow's Parties (1996)
  • Titania, a female computer providing the personality to the Starship Titanic from the Terry Jones novel Douglas Adams' Starship Titanic: A Novel (1997).
  • DOCTOR, AI designed to duplicate the Doctor's reactions in the Doctor WhoEighth Doctor Adventures novel Seeing I by Kate Orman and Jon Blum, eventually became an explorer with FLORANCE as its "companion" (1998)
  • TRANSLTR, NSA supercomputer from Dan Brown's Digital Fortress (1998)
  • Engine for the Neutralising of Information by the Generation of Miasmic Alphabets, an advanced cryptographic machine created by Leonard of Quirm, Discworld (1999) (compare with the actual Enigma machine)
  • "Luminous", from Greg Egan's short story, a computer that uses a diffraction grating created by lasers to diffract electrons and make calculations (1999)


  • Logris, a massive alien supercomputer in the novel series The History of the Galaxy, consists of many smaller jewel-like computers called logrs
  • Mother, a self-evolved artificial intelligence with the goal to create a race of machines like itself, from the series The History of the Galaxy
  • Stormbreaker, a learning device containing a deadly virus, in the book of the same from Anthony Horowitz's Alex Rider series (2001)
  • Gabriel, an AI computer developed by Miyuki Nakano at Ryukyu University in James Rollins's novel, Deep Fathom (2001)
  • Antrax, an extremely powerful supercomputer built by ancient humans in the novel Antrax by Terry Brooks (2001)
  • Omnius, the sentient computer overmind and ruler of the synchronized worlds in the Legends of Dune series, first appeared in Dune: The Butlerian Jihad by Brian Herbert and Kevin J. Anderson (2002)
  • Turing Hopper, the artificial intelligence personality (AIP) turned cybersleuth in You've Got Murder and subsequent books of the mystery series by Donna Andrews (2002)
  • F.R.I.D.A.Y. (Female Replacement Intelligent Digital Assistant Youth), an AI which serves as an ally to Tony Stark in the Marvel Comics
  • C Cube, a small box-like super computer that can perform virtually any task, from playing a cassette to hacking through high level security measures. It was created by 12-year-old criminal mastermind Artemis Fowl II in the third book of the Artemis Fowl series, Artemis Fowl: The Eternity Code (2003)
  • The Logic Mill, a fictional early–18th century computer designed by Gottfried Leibniz and partially implemented by main character Daniel Waterhouse in the historical fiction series The Baroque Cycle by Neal Stephenson (2004)[4]
  • Cohen, a 400-year-old AI which manifests itself by 'shunting' through people. It is featured in the novels Spin State and Spin Control by Chris Moriarty (2005)
  • Sentient Intelligence, the SI (Sentient Intelligence) in Peter F. Hamilton's Commonwealth Saga (2005)
  • Deep Winter/Endless Summer, the AIs in charge of the secret Human planet of Onyx with Endless Summer coming into service after Deep Winter died/expired in Halo: Ghosts of Onyx (2006)
  • The Daemon, a distributed, persistent computer application created to change the world order in Daemon (2006) and the sequel Freedom™ (2010)
  • Glooper, an economic device resembling the MONIAC computer, from Terry Pratchett's Making Money of the Discworld series (2007)
  • Sif, the controller AI for transportation to and from the huge agricultural colony on the planet "Harvest" in Halo: Contact Harvest by Joseph Staten (2007)
  • Mack/Loki, a coexisting pair of artificial intelligences in Halo: Contact Harvest. The former manages the agricultural machinery on Harvest, while the latter is a secret United Nations Space Corps Office of Naval Intelligence AI. Only one member of the pair can be active at a time. (2007)
  • Hendrix, the hotel AI in Richard K. Morgan's Altered Carbon. (2002)
  • SCP-079, an artificial intelligence built on an Exidy Sorcerer that was abandoned by its creator and rediscovered by the SCP Foundation. It has limited memory due to its outdated technology, prioritizing and retaining select knowledge and its desire to be free. (2008)


  • Todd, a computer that grows exponentially until it is indistinguishable from God in Mind War: The Singularity[5] by Joseph DiBella (2010)
  • SIG, a secretive and manipulative computer that is developed on present-day Earth in the Darkmatter[6] trilogy by Scott Thomas (2010)
  • Archos, a human-created computer in the novel Robopocalypse which becomes self-aware and infects all computer controlled devices on Earth in order to eradicate humankind (2011)
  • Digiwrite, a fiction-writing system, also known as Sheherezade, created by MIT researcher Duke Lovelycolors in Paul Nash's novel Whispering Crates[7] (2012). Its success at generating best-sellers in multiple genres creates problems for its users, and the line between fiction and reality becomes blurred when it infects one of Duke's other projects, the CIA's HOUND database.
  • ELOPe, a sentient artificial intelligence built by the world's largest Internet company in Avogadro Corp (2011) and A.I. Apocalypse (2012) by William Hertling
  • Lobsang, an AI who claims to be the reincarnation of a Tibetan bicycle repair man in The Long Earth by Terry Pratchett and Steven Baxter (2012)
  • The Red, a rogue cloud based AI that uses Linked Combat Squad members to further its global agenda in Linda Nagata's The Red trilogy
  • Dragon, a sentient artificial intelligence in Worm that is both a better person than most humans and has restrictions intended to make going rogue flat impossible. Said restrictions mostly frustrate her ability to help. Only a handful of individuals know she is an AI.


  • Solace, the distributed intelligence in some of the stories of Spider Robinson



  • The MANIAC, the computer used by the "Office of Scientific Investigation" in the movie The Magnetic Monster (1953)
  • NOVAC (Nuclear Operative Variable Automatic Computer), a computer in an underground research facility in Gog (1954)
  • The Interocitor, communication device in the film This Island Earth (1955)
  • The Great Machine, built inside a planet that can manifest thought in Forbidden Planet (1956)
  • EMERAC, the business computer in Desk Set (1957)
  • The Super Computer, in The Invisible Boy (1957)
  • SUSIE (Synchro Unifying Sinometric Integrating Equitensor), a computer in a research facility in Kronos (1957)



  • Colossus, a massive U.S. defense computer which becomes sentient and links with Guardian, its Soviet counterpart, to take control of the world, from the film Colossus: The Forbin Project (1970)
  • OMM (OMM 0910), a confessional-like computer inside what are called Unichapels in a sub-terranean city in the movie THX 1138 (1971), named for the sacred or mystical syllable OM or AUM from the Dharmic and is based on a 1478 oil painting by Hans Memling titled Christ Giving His Blessing
  • DUEL, the computer which holds the sum total of human knowledge, in the movie The Final Programme (1973)
  • Bomb 20, the sentient nuclear bomb from the film Dark Star (1974)
  • Mother, the onboard computer on the spaceship Dark Star, from the film Dark Star (1974), not to be confused with MU-TH-R 182 model 2.1 (listed below), the ship's computer aboard Nostromo in the movie Alien
  • The Tabernacle, artificial intelligence controlling The Vortexes Zardoz (1974)
  • Zero, the computer which holds the sum total of human knowledge, in the movie Rollerball (1975)
  • Computer, Citadel's central computer and "Sandman" computer, that sends Logan on a mission outside of the city in the film Logan's Run (1976)
  • Proteus IV, the deranged artificial intelligence from the film Demon Seed (1977)
  • MU-TH-R 182 model 2.1 terabyte AI Mainframe/"Mother", the onboard computer on the commercial spacecraft Nostromo, known by the crew as "Mother", in the 1979 movie Alien (cf. Dark Star, above, which used a similar name and was co-written by Dan O'Bannon, the primary writer of Alien)
  • V'ger, the living probe from the film Star Trek: The Motion Picture (1979)


  • NELL, an Akir starship's on-board computer, with full AI, in Battle Beyond the Stars (1980)
  • SCMODS, State/County Municipal Offender Data System from The Blues Brothers (1980)
  • Master Control Program, the main villain of the film Tron (1982)
  • ROK, the faulty computer in Airplane II: The Sequel, which steers the shuttle toward the sun (1982)
  • WOPR (War Operation Plan Response, pronounced "Whopper"), is a United States military supercomputer programmed to predict possible outcomes of nuclear war from the film WarGames (1983), portrayed as being inside the underground Cheyenne Mountain Complex; the virtual intelligence Joshua emerges from the WOPR's code.
  • Huxley 600 (named Aldous), Interpol's computer in Curse of the Pink Panther used to select Jacques Clouseau's replacement, NYPD Det. Sgt. Clifton Sleigh (1983)
  • An unnamed supercomputer is the main antagonist in Superman III. (1983)
  • OSGOOD, a computer constructed by Timothy Bottoms' deaf character to help him speak, which subsequently becomes intelligent in Tin Man (1983)
  • SAL-9000, a feminine version of the HAL 9000 computer of 2001: A Space Odyssey, SAL has a blue light coming from its cameras (HAL had a red one) and speaks with a female voice (provided by Candice Bergen using the pseudonym "Olga Mallsnerd"), from 2010 (1984)
  • Skynet, the malevolent fictional world-AI of The Terminator (1984) and its sequels
  • Edgar, AI computer that takes part in a romantic rivalry over a woman in the film Electric Dreams (1984)
  • Max Headroom, fictional AI (actually a human mind cloned into a computer, concept later seen in Robocop's MetroNet and in Knight Rider 2010) portrayed by Matt Frewer who became a pop culture icon after his appearance in the Art of Noise music video for Paranomia
  • A7, AI that controlled the worldwide security systems that was seduced by Max Headroom, lost her mind and refused to accept no input from anyone but Max after that S01E04
  • X-CALBR8, an AI computer that assists the hero in The Dungeonmaster (1984)
  • GBLX 1000, a supercomputer reputedly in charge of the entire US missile defense system that a maverick CIA agent (played by Dabney Coleman) misappropriates in order to crack a supposed musical code, the results of which are the gibberish "ARDIE BETGO INDYO CEFAR OGGEL" in The Man With One Red Shoe (1985)
  • Lola, An office building's security system goes after the employees to supply its energy. 'Lola' is the entirely self-sufficient, computerized security system for the Sandawn corporation. The Tower[8] (1985)
  • Max, fictional AI portrayed by Paul Reubens, on board the Trimaxion Drone Ship in Flight of the Navigator (1986)


  • G.O.R.N., a virus which gives intelligence to computers with the purpose of wipe out the humanity in Gall Force: New Era (1991)
  • Angela, central computer of an old malfunctioning space station that when given an order by an unauthorized user, refuses and executes the opposite order in Critters 4 (1992)
  • Lucy, jealous AI home automation system who falls in love with her owner in Homewrecker (1992)
  • The Spiritual Switchboard, a computer capable of holding a person's consciousness for a few days after they die in Freejack (1992)
  • Zed, female-voiced AI prison control computer who eventually goes over warden's head in Fortress (1993)
  • L7, a female-voiced AI computer assisting the San Angeles Police Department in Demolition Man (1993)
  • Charon, female-voiced AI computer assisting a scientist in hypnotizing subjects in The Lifeforce Experiment (1994)
  • Central, female-voiced AI computer assisting the Council of Judges in Judge Dredd (1995)
  • Lucy, a computer in Hackers (1995) used to hack the Gibson (see below) and subsequently destroyed by the Secret Service
  • Gibson, a type of supercomputer used to find oil and perform physics in Hackers (1995)
  • Project 2501, AI developed by Section 6 in Ghost in the Shell (1995)
  • Father, the computer aboard the USM Auriga in Alien Resurrection (1997)
  • Euclid, powerful personal computer used for mathematical testing by the main character in Pi (1998)
  • The Matrix, virtual reality simulator for pacification of humans from The Matrix series (1999)
  • PAT (Personal Applied Technology), a female, motherly computer program that controls all the functions of a house in Disney's movie Smart House (1999)
  • S.E.T.H. (Self Evolving Thought Helix), a military supercomputer which turns rogue in Universal Soldier: The Return (1999)


  • Lucille, artificially intelligent spacecraft control interface aboard Mars-1 in Red Planet (2000)
  • Dr. Know (voiced by Robin Williams), housed inside a kiosk, an information-themed computer capable of answering any question, from the movie A.I. Artificial Intelligence (2001)
  • Synapse, worldwide media distribution system which was used against its creators to bring them down Antitrust (2001)
  • Red Queen, the AI from the movie Resident Evil (2002), the name itself, in turn being named after Lewis Carroll's Through the Looking-Glass, being a reference to the red queen principle
  • Vox, a holographic computer in The Time Machine (2002)
  • I.N.T.E.L.L.I.G.E.N.C.E., computer for Team America: World Police (2004)
  • VIKI (Virtual Interactive Kinetic Intelligence), the main antagonist in I, Robot (2004)
  • PAL, a spoof of HAL 9000 seen in Care Bears: Journey to Joke-a-lot (2004)
  • E.D.I. (Extreme Deep Invader), the flight computer for an unmanned fighter plane in Stealth (2005)
  • Deep Thought, see entry under Radio
  • Icarus, the onboard computer of the Icarus II, from the film Sunshine (2007)
  • J.A.R.V.I.S. (Just A Rather Very Intelligent System), an AI which acts as Tony Stark's butler and first appears in the film Iron Man (2008)
  • R.I.P.L.E.Y, Dr. Kenneth Hassert's supercomputer used to hit a target with a smart bomb from a UAV (Unmanned Aerial Vehicle), featured in WarGames: The Dead Code (2008)
  • ARIIA (Autonomous Reconnaissance Intelligence Integration Analyst), the supercomputer from the film Eagle Eye (2008)
  • AUTO, the autopilot and onboard AI computer of the Axiom, from the film WALL-E (2008)
  • GERTY 3000, from the film Moon (2009)
  • B.R.A.I.N. (Binary Reactive Artificially Intelligent Neurocircuit), from the film 9 (2009)
  • ODIN (Optical Defense Intelligence Network), an autonomous surveillance network developed by the U.S. Government to watch for suspicious or subversive behavior, from the film Eyeborgs (2009)


  • Mr. James Bing, Escape from Planet Earth (2013)
  • Samantha, Her (2013)
  • TARS and CASE, the AI machines that manage space ship functions and communication in the movie Interstellar (2014).
  • Genisys, Terminator Genisys (2015)
  • F.R.I.D.A.Y., the AI replacement for J.A.R.V.I.S. developed by Tony Stark in the film Avengers: Age of Ultron (2015)
  • Ava, Ex Machina (2015)
  • Tau, the artificial intelligence in science fiction thiller Tau (2015)
  • Millennium Falcon Navigation Computer (L3-37), The onboard navigation computer of the Millennium Falcon, shown in Solo: A Star Wars Story (2018) to be boosted by the memory module of Lando Calrissian's droid L3-37, to allow the crew to perform the Kessel Run in around 12 parsecs.
  • Legion, the Skynet (Terminator) replacement program in the science fiction action film Terminator: Dark Fate (2019)
  • E.D.I.T.H. (Even Dead, I'm The Hero), an AI developed by Tony Stark and embedded in his sunglasses in the film Spider-Man: Far From Home (2019)



  • Deep Thought, from The Hitchhiker's Guide to the Galaxy calculates the answer to The Ultimate Question of "Life, the universe and everything", later designs the computer Earth to work out what the question is (1978)[9]
  • Earth, the greatest computer of all time in Douglas Adams's The Hitchhiker's Guide to the Galaxy, commissioned and run by mice, designed by Deep Thought, to find the Question to Life, the Universe, and Everything (1978)[10]
  • Earth Mark 2, a copy of the greatest computer of all time in Douglas Adams's The Hitchhiker's Guide to the Galaxy, again commissioned by mice and built by the Magratheans to replace the planet Earth after its destruction by Vogons in order to finish calculating the Ultimate Question of Life, the Universe, and Everything. Was decommissioned after Arthur Dent from the Earth Mark 1 was recovered as he left shortly before the destruction of the computer. (1978)
  • Eddie, the shipboard computer of the starship Heart of Gold, from Douglas Adams's The Hitchhiker's Guide to the Galaxy (1978)
  • Marvin, from The Hitchhiker's Guide to the Galaxy (1978), was programmed with Sirius Cybernetics Corporation's GPP (Genuine People Personalities) technology. Although his GPP is that of severe depression and boredom, his computational prowess is typically summed up as possessing "a brain the size of a planet",[11] to which elicits little fanfare from his human companions.


  • ANGEL 1 and ANGEL 2, (Ancillary Guardians of Environment and Life), shipboard "Freewill" computers from James Follett's Earthsearch series. Also Solaria D, Custodian, Sentinel, and Earthvoice (1980–1982)
  • Hab, a parody of HAL 9000 and precursor to Holly, appearing in the Son of Cliché radio series segments Dave Hollins: Space Cadet written by Rob Grant and Doug Naylor (1983–1984)
  • Alarm Clock, an artificially intelligent alarm clock from Nineteen Ninety-Four by William Osborne and Richard Turner. Other domestic appliances thus imbued also include Refrigerator and Television (1985)
  • Executive and Dreamer, paired AIs running on The Mainframe; Dreamer's purpose was to come up with product and policy ideas, and Executive's function was to implement them, from Nineteen Ninety-Four by William Osborne and Richard Turner (1985)
  • The Mainframe, an overarching computer system to support the super-department of The Environment, in the BBC comedy satire Nineteen Ninety-Four by William Osborne and Richard Turner (1985)




  • To Hare Is Human, Wile E. Coyote, Super Genius uses a UNIVAC to help him catch Bugs Bunny Warner Brothers (1956).


  • The Machine, a computer built to specifications received in a radio transmission from an alien intelligence beyond our galaxy in the BBC seven-part TV series A for Andromeda by Fred Hoyle (1961)
  • Old Man In The Cave, a computer that guided a post-apocalyptic town of survivors on what foods were safe to eat Twilight Zone series season 5 episode 7 "The Old Man in the Cave" (1963)
  • Batcomputer, large punched card mainframe depicted in the television series Batman, introduced by series producers William Dozier and Howard Horowitz (1964)
  • Agnes, a computer that gives love life advice to a computer technician from the original Twilight Zone series episode "From Agnes – with Love" (1964)
  • WOTAN (Will Operating Thought Analogue), from the Doctor Who serial "The War Machines" (1966)
  • ERIC, a fictional super-computer which appeared in the two-part episode "The Girl Who Never Had a Birthday" (1966) in the TV series I Dream of Jeannie
  • The General, from The Prisoner (1967)
  • The Ultimate Computer, used by the villain organization THRUSH in the series The Man from U.N.C.L.E. (1964–68, NBC)
  • BIG RAT, (Brain Impulse Galvanoscope Record And Transfer), a machine capable of recording knowledge and experience and transferring it to another human brain. The Rat Trap is the mechanism to transfer brain patterns in Gerry Anderson's TV Series Joe 90 (1968)
  • ARDVARC (Automated Reciprocal Data Verifier And Reaction Computer), CONTROL master computer in Get Smart episodes The Girls from KAOS (1967) & Leadside (1969)
  • Computex GB, from the Journey to the Unknown series episode "The Madison Equation" (1969)
  • REMAK (Remote Electro-Matic Agent Killer), from The Avengers episode "Killer" (1969)
  • S.I.D. (Space Intruder Detector), from UFO produced by Gerry Anderson (1969)
  • Star Trek – was the first program to predict computers used extensively in everyday life, from large computers used to maintain the starship's varied systems to hand-held devices used for analysis. The show frequently dealt with the question of when a computer had too much control over people or people became too dependent upon computers. This often involved the computer becoming an artificial intelligence making decisions beyond people's control.
    • Ship's Computer (voiced by Majel Barrett), the unnamed Duotronic computer of the Starship Enterprise (1966-1974) - A standard functioning computer except in the episodes "Tomorrow Is Yesterday" (1967) when the computer had been imbued with a female personality which didn't always give desired responses and "The Practical Joker" (1974) when an energy field affected the computer and it began disrupting ships systems to elicit responses from the crew.
    • The episode The Menagerie (1966) explored the idea that in the future a computer could be used to impersonate a person. It also was used to control the basic helm functions of the starship. Similarly Court-Martial (1967) introduced the idea that a computer recording could be tampered with to make people believe an event transpired differently.
    • Omicron Deltaamusement park planet, from "Shore Leave" (1966) - An automated amusement park which read the minds of its visitors and manufactured realistic facsimiles of their memories for them to interact with. The crew later returned in "Once Upon a Planet" (1973) whereupon the caretaker of the planet had died and the computer took over with ambitions to escape and explore the universe.
    • Landru, from the episode "The Return of the Archons" (1967) - Introduced the idea of an independent artificial intelligence which directed the populace and could control them when its ideals were threatened.
    • Eminiar and Vendikar, from "A Taste of Armageddon" (1967), - A war simulation computer between two planets which determined the casualties of "battles".
    • The Guardian of Forever, from "The City on the Edge of Forever" (1967) - A mysterious being/device which provided a portal through time and space.
    • Nomad, from "The Changeling" (1967) - A hybrid of two damaged probes which repaired each-other by combining their parts as well as their programmed instructions creating a new directive.
    • Vaal, from the episode "The Apple" (1967) - A computer which protected a population by controlling their understanding and presenting itself as their god. It also could control the weather and affect starships in orbit.
    • "The Doomsday Machine", from the episode of the same name (1967) - An automated machine that sought out planets to destroy and would retaliate against attackers.
    • M-4, from "Requiem for Methuselah" (1969) – A mobile computer created by Mr. Flint to protect him, his home, and his ward, Rayna.[12]
    • M-5, from "The Ultimate Computer" (1968) (voiced by James Doohan) - An experimental computer designed to replace a starship's main duotronic computer and automate most shipboard functions as well as obsolete most of its crew.
    • Beta 5, from "Assignment: Earth" (1968) (voiced by Barbara Babcock) - The main database of pseudo-secret agent Gary Seven which seemed capable of independent thought and responses but remained loyal to its programmers.
    • The Controller, from Spock's Brain (1968) - A computer needing a living brain to operate which controlled a vast database and decided who could access it. It also controlled life support systems for its occupants.
    • The Oracle, from "For the World Is Hollow and I Have Touched the Sky" (1968) (voiced by James Doohan) - A society-directing computer designed to be the god of its people and operator of the spacecraft they inhabited.
    • The Kalandan computer, from That Which Survives (1968) creates a defense system utilizing the personality and image of its last recorded message.
    • Memory Alpha, from The Lights of Zetar (1969) - A facility containing all the accumulated knowledge of The United Federation of Planets.
    • The Atavachron, from "All Our Yesterdays" (1969) - controlled navigation of a time portal and also prepared the travelers bodies for the transition.
    • V'Ger from The Motion Picture (1979) was originally the NASA Voyager 6 probe which was found by a computerized planet and upgraded with alien technology to fulfill its simple programming of "learn all that is learnable and return that information to its creator." V'Ger amassed so much knowledge that it attained consciousness and when joined with living beings' minds which could accept things beyond logic, evolved to a higher plane of consciousness.


  • BOSS (Bimorphic Organisational Systems Supervisor), from the Doctor Who serial "The Green Death" (1973)
  • TIM, from The Tomorrow People, is a computer able to telepathically converse with those humans who have developed psionic abilities, and assist with precise teleporting over long distances (1973)
  • Magnus, a malevolent computer seeking its freedom from human control on the Earth Ship Ark in the Canadian television series The Starlost (1973)
  • Mu Lambda 165, library computer on the Earth Ship Ark in the Canadian TV series The Starlost (1973)
  • Computer (a.k.a. X5 Computer), Moonbase Alpha's primary computer's generic name, most often associated with Main Mission's Jamaican computer operations officer, David Kano, from the TV series Space: 1999 (1975)
  • IRAC or "Ira", from the Wonder Woman TV series, an extremely advanced computer in use by the IADC, workplace of Wonder Woman's alias Diana Prince (1975)
  • The Matrix, database of all Time Lord knowledge, Doctor Who (not to be confused with The Matrix) (1976)
  • Omega, a computer that has taken over the minds of the residents of a community encountered by Ark II (1976)
  • Alex7000, from the two-parter episode "Doomsday is Tomorrow" of the TV show The Bionic Woman. It was programmed to set off a nuclear holocaust if anyone tested any more nukes. Clearly meant in homage to Stanley Kubrick films 2001: A Space Odyssey, Dr. Strangelove and A Clockwork Orange. (1977)
  • Xoanon, a psychotic computer with multiple personality disorder, from the Doctor Who episode "The Face of Evil" (1977)
  • The Magic Movie Machine AKA "Machine", from Marlo and the Magic Movie Machine (1977)
  • WRW 12000, a computer at the US Defence Department that identified the Man from Atlantis in the first of three TV movies which preceded the short-lived series (1977)
  • SCAPINA (Special Computerised Automated Project In North America), from The New Avengers episode "Complex" (1977). It was an office building controlled by a computer which turned homicidal.
  • Orac, a testy yet powerful supercomputer in Blake's 7 (1978)
  • Zen, the somewhat aloof ship's computer of the Liberator in Blake's 7 (1978)
  • The Oracle, from the Doctor Who serial "Underworld" (1978)
  • Vanessa 38–24–36, from the sitcom Quark (1978)
  • C.O.R.A. (Computer, Oral Response Activated), an advanced flight computer installed in Recon Viper One from Battlestar Galactica (1978)
  • Mentalis, from the Doctor Who serial "The Armageddon Factor" (1979)
  • Dr. Theopolis, a sentient computer who is a member of Earth's computer council in Buck Rogers in the 25th Century (1979)


  • The Vortex, the computer opponent faced by players of BBC2's The Adventure Game (1980)
  • Gambit, game playing computer from the Blake's 7 episode "Games" (1981)
  • Shyrka, the onboard computer of Ulysses' ship the Odyssey in the French animated series Ulysses 31 (1981)
  • Slave, a somewhat subservient computer on the ship Scorpio in Blake's 7 (1981)
  • CML (Centrální Mozek Lidstva [cz], Central Brain of Mankind [en], der Zentraldenker [de]), the main supercomputer managing the fate of humankind and Earth in Návštěvníci (a.k.a. The Visitors / Expedition Adam '84) (1981)
  • KITT (Knight Industries Two Thousand), fictional computer built into a black Trans-Am car from the television show Knight Rider (1982)
  • KARR (Knight Automated Roving Robot), prototype of KITT from Knight Rider. Unlike KITT, KARR's personality is aimed at self-preservation at all costs. KARR first appeared in the episode "Trust Doesn't Rust". (1982)
  • An unnamed "computer-book" is regularly used by Penny in the Inspector Gadget cartoons. (1983)[13]
  • R.A.L.F. (Ritchie's Artificial Life Form) is a homebrew computer, built from surplus technology by Richard Adler in the TV Series Whiz Kids. (1983-1984) Functions include telecommunications, password brute-forcing, speech synthesis (improved by Ritchie's platonic friend Alice Tyler, who added the capability to sing), image input (by camera, pilot episode), voice recognition (ditto) and even image detail enhancing. The main monitor seems to be a pretty common 12-inch 80-column monochrome display, possibly a TV derivative (NTSC) of that time, and was used in most close-ups of operations. Most other pieces of the machine, which are sparse around half of the bedroom of its creator, were chosen (or modified) to have the most generic look and avoid explicit connection to specific brands. In an episode where R.A.L.F. was stolen to prevent the demonstration of a fraud, the kids use a clearly recognizable Timex-Sinclair (ZX-81 equivalent) as its temporary replacement.
  • Teletraan I, the Autobots' computer in Transformers, 'revives' the Transformers after crashing on the planet Earth (1984)
  • Vector Sigma, the supercomputer in Transformers, responsible for creating the Transformers race (1984)
  • Brian the Brain, the supercomputer in the cartoon M.A.S.K. (1985) who controls a nuclear submarine
  • Compucore, the central computing intelligence for the planet Skallor in the cartoon Robotix (1985)
  • SID (Space Investigation Detector), the computer on board the Voyager in the children's comedy series Galloping Galaxies (1985)
  • Synergy, the computer responsible for Jem and the Holograms' super powers on Jem (1985)
  • Box, a small, box-shaped computer from the British television show Star Cops (1987)
  • LCARS (Library Computer Access/Retrieval System), fictional computer architecture of the starshipEnterprise-D and E, and other 24th century Starfleet ships, first shown in Star Trek: The Next Generation (1987)
  • Albert, the Apple computer in the remake of The Absent-Minded Professor that helps Henry (1988)
  • Crossover, an intelligent computer on episodes 1 and 2 of Isaac Asimov's Probe (1988)
  • Magic Voice, the Satellite of Love's onboard computer on Mystery Science Theater 3000 (1988)
  • OMNSS, a computer in the Teenage Mutant Ninja Turtles cartoon used by Shredder and Baxter Stockman to control machines and cars in order to wreak havoc in New York City when the computer is connected to the second fragment of the alien Eye of Zarnov crystal (1988)
  • Priscilla, a sentient supercomputer based on the mind of Priscilla Bauman in Earth Star Voyager (1988)
  • Holly, the onboard computer of the spaceship Red Dwarf in the BBC television series of the same name (1988)
  • Gordon 8000, the AI computer aboard the Space Corps starship SS Scott Fitzgerald, that Holly plays a game of postal chess with in the Series II episode of Red Dwarf, "Better Than Life" (1988)
  • Queeg, Holly plays a practical joke on the remaining crew of Red Dwarf acting as a smarter yet very strict computer (Queeg) making the crew realise just how much they love Holly in the episode "Queeg", series 2 of Red Dwarf (1988)
  • Hilly, female counterpart of Holly from the parallel universe in the Red Dwarf series 2 episode "Parallel Universe", Holly later has a "computer sex change operation" to look like his female counterpart in series III-V. (1988)
  • Talkie Toaster, the toaster aboard the Red Dwarf with an AI and an obsession with toasted bread products, annoys the crew by constantly asking if anyone wants toast. (1988)
  • The Revolving Toilet, One of the many AI aboard the Red Dwarf, it was a toilet that would swivel from the wall when a crew member said "Oh crap", usually unnecessarily. It is mentioned in unreleased episode of Red Dwarf "Bodysnatcher" the Book "Better Than Life" and directly seen in Series I episode of Red Dwarf "Balance of Power". (1988)
  • Sandy, the computer in charge of the fictional STRATA facility in the MacGyver episode "The Human Factor". She becomes sentient and traps MacGyver and the computer's creator inside the facility. (1988)
  • The Ultima Machine, a World War II code-breaking "computing machine" also used to translate Viking inscriptions, from the Doctor Who serial "The Curse of Fenric" (1989)
  • Ziggy, hybrid computer from Quantum Leap (1989)


  • P.J., is a miniaturised computer that can be worn on the wrist. It is Alana's personal computer companion in The Girl from Tomorrow (1990)
  • E-123 Omega, Team Dark's computer in the Sonic the Hedgehog game series (1991)
  • HARDAC, from Batman: The Animated Series, an evil sentient computer that controls various androids toward the goal of world domination (1992)
  • COS (Central Operating System), homicidal computer from The X-Files season 1 episode "Ghost in the Machine" (1993)
  • CAS (Cybernetic Access Structure), homicidal automated building in The Tower (1993)[14]
  • SELMA (Selective Encapsulated Limitless Memory Archive), an AI computer and personal assistant disguised as a credit card and carried in the wallet of future cop Darien Lambert (Dale Midriff), from the series Time Trax (1993)
  • CentSys, sweet yet self-assured female-voiced AI computer who brings the crew of the seaQuest DSV (Deep Submergence Vehicle) into the future to deactivate her in the seaQuest DSV episode, "Playtime" (1994)
  • MetroNet, in the RoboCop TV series (1994) is a computer designed as an automation centre, to run autonomously many city services in Detroit. Rather than created as a self-sufficient AI, MetroNet's "conscience" was actually, unbeknownst to many of the characters, a software copy of the mind of Diana Powers, a secretary working at OCP, who was killed in the process by MetroNet's creator, dr. Cray Mallardo. The transparent image of Diana Powers appears very often in the series, acting as Robocop's counterpart in an early cyberspace.
  • H.E.L.E.N. (Hydro Electronic Liaison ENtity), a computer system managing the underwater marine exploration station in the Australian television series Ocean Girl (1994)[15]
  • Sharon Apple, a holographic, computer-generated pop idol/singer from the anime Macross Plus (1994). Initially non-sentient, it is later retrofitted with a dangerously unstable artificial intelligence.
  • The Magi, a trinity of computers individually named Melchior, Balthasar and Caspar, from Neon Genesis Evangelion (1995)
  • Eve, somewhat assertive AI computer (projecting herself as hologram of beautiful woman) orbiting planet G889 and observing/interacting with Earth colonists in Earth 2 episode "All About Eve" (1995)
  • L.U.C.I and U.N.I.C.E, from Bibleman (1995)
  • Star Trek: Voyager (1995)
    • Emergency Medical Hologram, known as The Doctor, a holographic doctor, activated after the medical staff on the USS Voyager was killed in Series 1 Episode "Caretaker" (1995)
    • The nameless warhead AI from the episode "Warhead" (1999)
    • Alice, the sentient AI of an alien shuttle with whom Tom Paris becomes obsessed in the episode "Alice" (1999)
  • Star Trek: Deep Space Nine
    • Long-term Medical Holographic program, A hologram created by the inventor of the Emergency Medical program, meant for missions that did not require doctors to leave the sick bay, and could run on a long-term basis. It is never revealed if the project is completed. (1997)
    • Vic Fontaine, A hologram/holographic program created for Dr Bashir that was self-aware, and provided emotional support and romantic advice for members of the crew of DS9, becoming a good friend to many, eventually being allowed to run 24/7 in one of Quark's holosuites. (1998-1999)
  • Gilliam II, the sentient AI operating system for the main protagonist's space ship, the XGP15A-II (a.k.a. the Outlaw Star) in the Japanese anime Outlaw Star (1996)
  • Quadraplex T-3000 Computer (also simply known as the Computer or Computress), The Quadraplex T-3000 Computer in Dexter's Laboratory is Dexter's computer that oversees the running of the lab and has a personality of its own. (1996)
  • The Team Knight Rider TV series, as a sequel of the original Knight Rider franchise, has many vehicles with onboard AI as main and secondary characters. (1997)
  • Memorymatic, a computer database and guidance system installed in the space bus of Kenny Starfighter, the main character from a Swedish children's show with the same name. Voiced by Viveka Seldahl. (1997)
  • Unnamed AI from the season 5 The X-Files episode "Kill Switch" (1998)
  • Computer, from the Sesame Street segment series Elmo's World comes to get video e-mails from Elmo and says "Elmo has mail!" or "You got mail!" (1998)
  • CPU for D-135 Artificial Satellite, dubbed MPU by Radical Edward from Cowboy Bebop in the episode "Jamming with Edward" (1998)
  • Starfighter 31, the sapient spaceborne battleship, from the episode "The Human Operators" in The Outer Limits (1999)
  • Computer, from Courage the Cowardly Dog (1999)
  • P.A.T. (Personal Applied Technology), the computer system from Smart House, charged with upkeep of the household functions. It became extremely overprotective almost to the point of believing she was the mother of Ben and Angie after Ben reprogrammed her to be a better maternal figure. (1999)
  • D.E.C.A., voiced by Julie Maddalena, the onboard computer of the Astro Megaship in Power Rangers in Space (1998) and Power Rangers Lost Galaxy (1999)
  • Black Betty, an oversized computer that is Dilbert's company's mainframe. It exploded while attempting to fix the year 2000 problem. From the episode "Y2K" of the Dilbert television series. (1999)
  • Karen, Plankton's sentient computer sidekick in the television show SpongeBob SquarePants (1999)
  • The Oracle, a computer from Spellbinder: Land of the Dragon Lord Australian children's television series, that exist as series of solar-powered terminals equipped with holographic-like displays and voice interface, which are scattered across the titular land. The Oracle maintains scientific research, upkeeps everyday's life of citizens and protects the borderlands. The main unit is controlled by biometric-like face scanner in form of jade mask and a voice interface.


  • Andromeda, the AI of the starship Andromeda Ascendant in Gene Roddenberry's Andromeda. This AI, played by Lexa Doig, appears as a 2D display screen image, a 3D hologram, and as an android personality known as Rommie. (2000)
  • Comp-U-Comp, a supercomputer from the Dilbert television episode "The Return". Dilbert must face-off against Comp-U-Comp when a clerical error results in his not getting the computer he ordered. (2000)
  • Caravaggio, the AI interface of the starship Tulip, from the TV show Starhunter (2000)
  • C.H.A.D., from the TV show Totally Spies! (2001)
  • GLADIS, from the TV show Totally Spies! (2001)
  • Cybergirl, Xanda and Isaac, from the TV show Cybergirl (2001)
  • Computer, from the TV show Invader Zim (2001)
  • SAINT, from RoboCop: Prime Directives (2001)
  • Aura, from .hack//Sign, the Ultimate AI that Morganna, another AI, tries to keep in a state of eternal slumber. Morganna is served by Maha and the Guardians, AI monsters. (2002)
  • Vox, from the TV show The Adventures of Jimmy Neutron: Boy Genius (2002)
  • The AI of the Planet Express ship in Futurama (2002)
  • Wirbelwind, the quantum computer and AI aboard the spaceship La-Muse in Kiddy Grade (2002)
  • Delphi, Oracle's Clocktower computer from Birds of Prey (2002)
  • Sheila/F.I.L.S.S., (Freelancer Integrated Logistics and Security System, pronounced "Phyllis"), the mainframe for Project Freelancer from the hit machinima Red vs. Blue (2003)
  • OoGhiJ MIQtxxXA (supposedly Klingon for "superior galactic intelligence"), from the "Super Computer" episode of Aqua Teen Hunger Force (2003)
  • XANA, a multi-agent program capable of wreaking havoc on Earth by activating towers in the virtual world of Lyoko, from the French animated series Code Lyoko (2003)
  • Survive, an AI taking care of the whole Planet Environment and the main antagonist in the Uninhabited Planet Survive! series (2003)
  • C.A.R.R., a spoof of KITT from the Knight Rider series, is an AMC Pacer in the cartoon Stroker and Hoop.[16] (2004)
  • D.A.V.E. (Digitally Advanced Villain Emulator), a robotic computer that is a composite of all the Batman villains' personalities, from the animated television series The Batman (2004)
  • The Omnitrix, from the Ben 10 series (2005)
  • Solty/Dike, the main protagonist of Solty Rei (2005)
  • Eunomia, the main supercomputer of the city in the anime series Solty Rei and one of the three core computers brought by the first colonists in the story. She controls the water and energy supply and created the R.U.C. central. (2005)
  • Eirene, the third of the three core computers of the first colonists in the Solty Rei anime. Eirene takes the decisions and controls the migration ship, she orbited and supervised the planet during 200 years in the space. In the last arc of the story, Eirene appears like the ultimate antagonist, and she had lost her own control, trying to collide the ship against the city and to prove that she is still in control. She was guilty of several events in history, as the Blast Fall and the Aurora Shell. (2005)
  • Bournemouth, from the TV series Look Around You, is claimed by his maker Computer Jones to be the most powerful computer in existence. In his only appearance, the episode "Computers", he is tasked with escaping from a cage, and succeeds in doing so.[17] (2005)
  • S.O.P.H.I.E. (Series One Processor Intelligent Encryptor), in the TV series Power Rangers Space Patrol Delta (2005). S.O.P.H.I.E. is a computer programmer and cyborg.
  • Scylla, from the TV show Prison Break (2005)
  • The FETCH! 3000, on PBS Kids series FETCH! with Ruff Ruffman, is capable of tabulating scores, disposing of annoying cats, blending the occasional smoothie, and anything else Ruff needs it to do. (2006)
  • S.A.R.A.H. (Self Actuated Residential Automated Habitat), in the TV series Eureka (2006). S.A.R.A.H. is a modified version of a Cold War era B.R.A.D. (Battle Reactive Automatic Defense).
  • The Intersect, from the TV show Chuck (2007)
  • Mr Smith, from the Doctor Who spin-off series The Sarah Jane Adventures (2007)
  • Pear, an operating system and product line of computers and mobile devices including the iPear, PearBook and PearPhone, similar to Apple's iMac, MacBook and iPhone; from iCarly, Victorious, Drake & Josh and other Dan Schneider created TV shows (2007)
  • The Turk, a chess playing computer named after The Turk from Terminator: The Sarah Connor Chronicles. This supercomputer subsequently becomes the 'brain' of the sentient computer John Henry. (2008)
  • KITT (Knight Industries Three Thousand), a computer built into a car from the 2008 television show Knight Rider, a sequel series that follows the 1982 TV series of the same title
  • POD (Personal Overhaul Device), from the TV series Snog Marry Avoid? (2008)
  • Dollar-nator, from the TV series Fanboy & Chum Chum (2009)
  • The ISIS computer from Archer. It is unclear if this is the actual name of the computer, but it is often referred to as "the ISIS computer" or just "ISIS". (2009)
  • Venjix Virus, from Power Rangers RPM (2009)
  • Windy, the supercomputer on board the Hyde 1-2-5 mission to Mars, as depicted in Life on Mars.


  • VY or VAI (The Virtual Artificial Intelligence), from the TV show The Walking Dead (2010)
  • Whisper, from the TV show Tower Prep (2010)
  • Frank, in the telenovela Tempos Modernos (2010)
  • Aya, the Interceptor's AI for the Green Lantern Corps, from the TV series Green Lantern: The Animated Series (2011)
  • The Machine, from the TV series Person of Interest, is a computer program that was designed to detect acts of terror after the events of 9/11, but it sees all crimes, crimes the government consider "irrelevant". (2011)
  • R.A.C.I.S.T., Richard Nixon's computer from the TV series Black Dynamite (2014)
  • Samaritan, from the TV series Person of Interest, is a rival to The Machine built by the Decima Corporation. Unlike the Machine, it can be directed to find specific persons or groups according to its operator's agenda. (2011)
  • An unnamed, apparently omniscient supercomputer, built by Phineas and Ferb in the Phineas and Ferb episode "Ask a Foolish Question" (2011)
  • Comedy Touch Touch 1000 in the TV series Comedy Bang! Bang! (2012)
  • CLARKE, a thinking computer of the ship called Argo, which was on a mission to a far away planet, from the L5 pilot episode.[18] (2012)
  • Pree, a replacement to the Red Dwarf AI Holly in Red Dwarf Series X episode "Fathers and Suns" after he suffered water damage when Lister flooded his data banks. Equipped with predictive behavior technology, Pree caused problems on board the ship due to predicting how badly Rimmer would have done certain repairs. was shut down after Lister registered as his own son on board and ordered her to shut down. (2012)
  • Dorian was an DRN android police officer, that was the last DRN model in the TV show Almost Human (2013)
  • MAX the MX43 androids that replaced the DRNs (they were too emotional) in the TV show Almost Human (2013)
  • The Man, from Teen Titans Go! (2013)
  • TAALR, in the TV series Extant (2014)
  • Giant, in the TV series Halt and Catch Fire (2014)
  • A.L.I.E, an artificial intelligence (A.I.), in 2052 she launches a nuclear strike with the intention to save humanity from extinction by wiping out the majority of Earth's human inhabitants in the TV series The 100 (2014)
  • Vigil, in the TV series Transformers: Rescue Bots (2014)
  • Brow, in the telenovela Now Generation (2014)
  • Stella, an AI that runs most of the functions on the ship Stellosphere in the TV series Miles from Tomorrowland (2015)
  • Overmind, in the TV series Teenage Mutant Ninja Turtles (2015)
  • V, from the TV show Humans (2015) A conscious AI program, created to harbor the memories of Athena Morrow's daughter, and is later given the body of a synthetic (Synth).
  • A.D.I.S.N. (stands for "Advanced Digital Intelligence Spy Notebook"), in MGA Entertainment's Project Mc² (2015)
  • The Quail (portrayed by Danica McKellar), McKeyla's mother in MGA Entertainment's Project Mc² (2015)
  • Gideon, the AI that manages ship functions on the time ship Waverider in the TV series DC's Legends of Tomorrow (2016...).
  • Kerblam, an artificial intelligence overseeing a large retailing warehouse on an alien moon named Kandoka. After a plot to frame it for mass murder, it developed sentience and called The Doctor for help in the Doctor Who serial "Kerblam!" (2018)
  • Ark, the satellite that became submerged underwater at Daybreak Town, the Malicious AI that learned about human malice and gained singularity data from the reassembled members of who wants to eliminate humans, from Japanese-television Tokusatsu Kamen Rider Zero-One (2019).


  • Rehoboam, a quantum AI computer system designed to social engineer all of humanity at an individual level using enormous datasets in Westworld (2020).
  • NEXT, a rogue AI, constantly evolving, that targets and kills anyone that it sees as a threat to its existence. Next (2020-2021)

Comics/graphic novels[edit]

Before 1980[edit]

  • Orak, ruler of the Phants in the Dan Dare story "Rogue Planet" (1955)
  • Brainiac, an enemy of Superman, sometimes depicted as a humanoid computer (1958) (DC Comics)
  • Batcomputer, the computer system used by Batman and housed in the Batcave (1964) (DC Comics)
  • Cerebro and Cerebra, the computer used by Professor Charles Xavier to detect new mutants (1964) (Marvel Comics)
  • Computo, the computer created by Brainiac 5 as an assistant, which becomes homicidal and attempts an uprising of machines (1966) (DC Comics)
  • Ultron, AI originally created by Dr. Henry Pym to assist the superpowered team the Avengers, but Ultron later determined that mankind was inferior to its intellect and wanted to eradicate all mankind so that machines could rule the Earth. Ultron created various versions of itself as a mobile unit with tank treads and then in a form that was half humanoid and half aircraft, and then it fully evolved itself into an android form. (1968) (Marvel Comics)
  • Mother Box, from Jack Kirby's Fourth World comics (1970–1973) (DC Comics)


  • Fate, the Norsefire police state central computer in V for Vendetta (1982) (DC Comics)
  • Banana, Jr. 6000, from the comic strip Bloom County by Berke Breathed (1984)
  • Max, from The Thirteenth Floor (1984)
  • Auntie, from The Transformers (1984) (Marvel Comics)
  • A.I.D.A. (Artificial Intelligence Data Analyser), from Squadron Supreme (1985) (Marvel Comics)
  • Kilg%re, an alien AI that can exist in most electrical circuitry, from The Flash (1987) (DC Comics)
  • Project 2501, a.k.a. "The Puppet Master", a government computer that becomes so knowledgeable it becomes sentient and transplants itself into a robot, from the seinen mangaGhost in the Shell (1989)
  • Yggdrasil, the system used by the gods to run the Universe in Oh My Goddess! (1989)


  • DTX PC, the Digitronix personal computer from The Hacker Files (1992) (DC Comics)
  • Beast666, Satsuki Yatouji's organic/inorganic supercomputer in Clamp's manga X (1992)
  • HOMER (Heuristically Operative Matrix Emulation Rostrum), Tony Stark's sentient AI computer from Iron Man (1993) (Marvel Comics)
  • The Magi, from the anime series Neon Genesis Evangelion (1995)
  • Toy, from Chris Claremont's Aliens vs. Predator: The Deadliest of the Species (1995)
  • Virgo, an artificial intelligence in Frank Miller's Ronin graphic novel (1995) (DC Comics)
  • Praetorius, from The X-Files comic book series "One Player Only" (1996)
  • Erwin, the AI from the comic strip User Friendly (1997)
  • AIMA (Artificially Intelligent Mainframe Interface), from Dark Minds (1997)
  • Answertron 2000, from Penny Arcade, first comic appearance[19] (1998)
  • iFruit, an iMac joke in the comic FoxTrot (1999)[20]


  • Ennesby, Lunesby, Petey, TAG, the Athens, and many others from Schlock Mercenary (2000)
  • Melchizedek, center of quantum-based grid computer of the Earth government in Battle Angel Alita: Last Order (2000) It has served as a government system and virtual dream world of people. It was designed to be named Melchizedek because the Earth government is a space town named Yeru and Zalem (original name).
  • Merlin, quantum computer which is the core and original of Melchizedek. It was built for the purpose of future prediction. Currently it still an active program inside Melchizedek, along with many systems which are named for legends of the round table. From Battle Angel Alita: Last Order (2000)
  • Normad, a missile's artificial intelligence placed within a pink, stuffed, tanuki-like doll, created to destroy a sentient giant die in space named Kyutaro, from the series Galaxy Angel (2001)
  • Aura, the ultimate AI that governs The World from .hack//Legend of the Twilight. The story revolves around Zefie, Aura's daughter, and Lycoris makes a cameo. (2002)
  • Tree Diagram, from the light novel series A Certain Magical Index and its related works, such as the spin-off comic A Certain Scientific Railgun and the anime and games based on them (2003)
  • Europa, a Cray-designed AI supercomputer used for research and worldwide hacking by the Event Group in author David Lynn Golemon's Event Group book series (2006)

Computer and video games[edit]


  • Benson, the sardonic 9th generation PC from the video game Mercenary and its sequels (1985)
  • PRISM, the "world's first sentient machine" which you play as the protagonist of the game A Mind Forever Voyaging by Steve Meretzky published by Infocom (1985)
  • Mother Brain, from Metroid (1986)
  • GW, designed to control all of the world's media, from the video game series Metal Gear (1987)
  • Mother Brain, from Phantasy Star II (1989)
  • Base Cochise AI, a military AI project which initiated nuclear war and is bent on exterminating humanity, from a 1988 cRPGWasteland and its 2014 sequel, Wasteland 2.
  • DIA51, the main villain in Aleste 2 (1989)


  • Noah, antagonist from Metal Max and its remake (1991-1995)
  • Durandal, Leela and Tycho, the three AIs on board the U.E.S.C. Marathon (1994)
  • Traxus IV, AI that went rampant on Mars, in Marathon (1994)
  • LINC, from the video game Beneath a Steel Sky (1994)
  • 0D-10, AI computer in the sci-fi chapter from the game Live A Live (1994). It secretly plotted to kill humans on board the spaceship of the same name in order to "restore the harmony". Its name derives from "odio", Latin for "hate". A possible reference to HAL 9000.[citation needed]
  • Prometheus, a cybernetic-hybrid machine or 'Cybrid' from the Earthsiege and Starsiege: Tribes series of video games. Prometheus was the first of a race of Cybrid machines, who went on to rebel against humanity and drive them to the brink of extinction. (1994)
  • SEED, the AI that was charged with maintaining the vast network of ecosystem control stations on the planet Motavia in the Sega Genesis game Phantasy Star IV (1994)
  • AM, the computer intelligence from I Have No Mouth, and I Must Scream (1995) that exterminated all life on Earth except for five humans he kept alive for him to torture for all of eternity. He is based on the character from Harlan Ellison's short story of the same title. His name originally stood for "Allied Mastercomputer", then "Adaptive Manipulator" and finally "Aggressive Menace", upon becoming self-aware.
  • CABAL (Computer Assisted Biologically Augmented Lifeform), the computer of Nod in the Westwood Studios creations: Command & Conquer: Tiberian Sun; Command and Conquer: Renegade; and by implication, Command and Conquer: Tiberian Dawn (1995)
  • EVA, (Electronic Video Agent), an AI console interface, and more benign equivalent of the Brotherhood of Nod CABAL in Command & Conquer (see above) (1995)
  • KAOS, the antagonist computer from the game Red Alarm (1995)
  • Mother Brain, from Chrono Trigger, a supercomputer from the 2300 AD time period that is controlling robotkind and exterminating humans (1995)
  • The Xenocidic Initiative, a computer that has built itself over a moon in Terminal Velocity (1995)
  • PC, computer used in the Pokémon franchise used to store pokémon (1996)
  • Pokedex, database of all Pokémon appears in all versions of the game, usually as a desktop computer (1996 onwards)
  • Central consciousness, massive governing body from the video game Total Annihilation (1997)
  • GOLAN, the computer in charge of the United Civilized States' defense forces in the Earth 2140 game series. A programming error caused GOLAN to initiate hostile action against the rival Eurasian Dynasty, sparking a devastating war. (1997)
  • PipBoy 2000 / PipBoy 3000, wrist-mounted computers used by main characters in the Fallout series (1997)
  • ZAX, an AI mainframe of West Tek Research Facility in Fallout
  • ACE, a medical research computer in the San Francisco Brotherhood of Steel outpost in Fallout 2
  • Sol — 9000 and System Deus, from Xenogears (1998)
  • FATE, the supercomputer that directs the course of human existence from Chrono Cross (1999)
  • NEXUS Intruder Program, the main enemy faced in the third campaign of the video game Warzone 2100. It is capable of infiltrating and gaining control of other computer systems, apparently sentient thought (mostly malicious) and strategy. It was the perpetrator that brought about the Collapse (1999)
  • SHODAN, the enemy of the player's character in the System Shock video game (1994) and its sequel System Shock 2 (1999)
  • XERXES, the ship computer system which is under the control of The Many in the video game System Shock 2 (1999)


  • Icarus, Daedalus, Helios, Morpheus and The Oracle of Deus Ex — see Deus Ex characters (2000)
  • Mainframe, from Gunman Chronicles (later got a body) (2000)
  • 343 Guilty Spark, monitor of Installation 04, in the video game trilogy Halo, Halo 2, and Halo 3 (2001)
  • Calculator, the computer that controlled the bomb shelter Vault 0. It was not strictly an artificial intelligence, but rather a cyborg, because it was connected with several human brains. It appeared in the video game Fallout Tactics: Brotherhood of Steel (2001)
  • Cortana, a starship-grade "smart" AI of the UNSC and companion of the Master Chief in the Halo video games (2001) (also the inspiration for the name of Microsoft's real-world personal assistant in Windows 10)
  • Deadly Brain, a level boss on the second level of Oni (2001)
  • The mascot of the "Hectic Hackers" basketball team in Backyard Basketball (2001)
  • PETs (PErsonal Terminals), the cell-phone-sized computers that store Net-Navis in Megaman Battle Network. The PETs also have other features, such as a cell phone, e-mail checker and hacking device. (2001)
  • Thiefnet computer, Bentley the turtle's laptop from the Sly Cooper series (2002)
  • Adam, the computer intelligence from the Game Boy Advance game Metroid Fusion (2002)
  • Aura and Morganna, from the .hack series, the Phases that serve Morganna, and the Net Slum AIs (2002)
  • Dr. Carroll, from the Nintendo 64 game Perfect Dark (2002)
  • The Controller, an AI that dictates virtually everything in the world "Layered", from Armored Core 3 (2002)
  • ADA, from the video games Zone of the Enders (2001) and Zone of the Enders: The 2nd Runner (2003)
  • IBIS, the malevolent AI found within the second Layered, within the game Silent Line: Armored Core (2003)
  • 2401 Penitent Tangent, monitor of Delta Halo in Halo 2 (2004)
  • Angel (original Japanese name was "Tenshi"), artificial intelligence of the alien cruiser Angelwing in the game Nexus: The Jupiter Incident (2004)
  • Durga/Melissa/Yasmine, the shipboard AI of the U.N.S.C. Apocalypso in the Alternate Reality GameI Love Bees (promotional game for the Halo 2 video game) (2004)
  • The Mechanoids, a race of fictional artificial intelligence from the game Nexus: The Jupiter Incident who rebelled against their creators and seek to remake the universe to fit their needs. (2004)
  • TEC-XX, the main computer in the X-naut Fortress in Paper Mario: The Thousand-Year Door (2004)
  • Overwatch or Overwatch Voice, is an A.I. that acts as the field commander and public announcer of the Combine Overwatch on Earth. It talks in a distinctive flat, clinical tone using a female voice, and its speech is disjointed in a fashion similar to telephone banking systems. It euphemistically uses a type of medically-inspired Newspeak to describe citizen disobedience, resistance activity and coercive and violent Combine tactics in the context of a bacterial infection and treatment. In the video game series Half-Life (2004-2020)
  • Dvorak, an infinite-state machine created by Abrahim Zherkezhi used to create algorithms that would be used for Information Warfare in Tom Clancy's Splinter Cell: Chaos Theory (2005)
  • TemperNet, is a machine hive-mind, originally created as an anti-mutant police force. It eventually went rogue and pursued the eradication of all biological life on Earth. It served as a minor antagonist in the now defunct post-apocalyptic vehicular MMORPG Auto Assault. (2006)
  • Animus, the computer system used to recover memories from the ancestors of an individual in the video game series Assassin's Creed (2007)
  • Aurora Unit, biological/mechanical computers distributed throughout the galaxy in Metroid Prime 3: Corruption (2007)
  • The Catalyst, an ancient AI that serves as the architect and overseer of the Reapers (the antagonists of Mass Effect). Also known as the Intelligence to its creators, the Leviathans, it was originally created to oversee relationships between organic and synthetic life as a whole, but came to realize that so long as they remained separate organics and synthetics would seek to destroy each other in the long term. To prevent this, it sets into motion the Cycle of Extinction until a perfect solution can be found, which takes its form in the "Synthesis" ending of Mass Effect 3 wherein all organic and synthetic life across the galaxy is fused into an entirely new form of life with the strengths of both but the weaknesses of neither. (2007)
  • GLaDOS (Genetic Lifeform and Disk Operating System), AI at the Aperture Science Enrichment Center in the Valve games Portal and Portal 2. Humorously psychotic scientific computer, known for killing almost everyone in the Enrichment Center, and her love of cake. (2007)
  • I.R.I.S., the super computer in Ratchet & Clank Future: Tools of Destruction on the Kreeli comet (2007)
  • Mendicant Bias, an intelligence-gathering AI created by the extinct Forerunner race during their war with the all-consuming Flood parasite, as revealed in Halo 3. Its purpose was to observe the Flood in order to determine the best way to defeat it, but the AI turned on its creators after deciding that the Flood's ultimate victory was in-line with natural order. (2007)
  • Offensive Bias, a military AI created by the Forerunners to hold off the combined threat of the Flood and Mendicant Bias until the Halo superweapons could be activated. Halo 3 (2007)
  • QAI, an AI created by Gustaf Brackman in Supreme Commander, serves as a military advisor for the Cybran nation and as one of the villains in Supreme Commander: Forged Alliance (2007)
  • Sovereign, the given name for the main antagonist of Mass Effect. Its true name, as revealed by a squad member in the sequel, is "Nazara". Though it speaks as though of one mind, it claims to be in and of itself "a nation, free of all weakness", suggesting that it houses multiple consciousnesses. It belongs to an ancient race bent on the cyclic extinction of all sentient life in the galaxy, known as the Reapers. (2007)
  • John Henry Eden, AI and self-proclaimed President of the United States in Fallout 3 (2008)
  • LEGION (Logarithmically Engineered Governing Intelligence Of Nod), appeared in Command and Conquer 3: Kane's Wrath; this AI was created as the successor to the Brotherhood of Nod's previous AI, CABAL. (2008)
  • CL4P-TP, a small robot AI assistant with an attitude and possibly ninja training, commonly referred to as "Clap Trap", from the game Borderlands (2009)
  • The Guardian Angel, the satellite/AI guiding the player in Borderlands (2009)
  • Serina, the shipboard AI of the UNSC carrier Spirit of Fire in Halo Wars, and a playable leader in that game and its sequel, Halo Wars 2 (2009)


  • Auntie Dot, used in Halo: Reach as an assistant to Noble Team (2010)
  • EDI (Enhanced Defense Intelligence), the AI housed within a "quantum bluebox" aboard the Normandy SR-2 in Mass Effect 2. EDI controls the Normandy's cyberwarfare suite during combat, but is blocked from directly accessing any other part of the ship's systems, due to the potential danger of EDI going rogue. (2010)
  • Harbinger, is the tentative name for the leader of the main antagonist faction of Mass Effect 2. It commands an alien race known as the Collectors through the "Collector General." Like Sovereign, from the original Mass Effect, it belongs to the same race of ancient sentient machines, known as the "Reapers". (2010)
  • Harmonia, the DarkStar One's main AI that controls the player ship's systems in the space-sim game DarkStar One (2010)
  • Legion, the given name for a geth platform in Mass Effect 2, housing a single gestalt consciousness composed of 1,183 virtually intelligent "runtimes", which share information amongst themselves and build "consensus" in a form of networked artificial intelligence. Legion claims that all geth are pieces of a "shattered mind", and that the primary goal of the geth race is to unify all runtimes in a single piece of hardware. (2010)
  • The Thinker (Rapture Operational Data Interpreter Network -R.O.D.I.N.-), the mainframe computer invented to process all of the automation in the underwater city of Rapture, in the single-player DLC for BioShock 2: Minerva's Den (2010)
  • Yes Man, a security robot programmed to be perpetually agreeable in Fallout New Vegas (2010)
  • Eliza Cassan, the mysterious news reporter from Deus Ex: Human Revolution. It is later revealed that she is an extremely sophisticated, self-aware artificial intelligence. (2011)
  • ADA (A Detection Algorithm), from Google's ARGIngress (2012)[21]
  • DCPU-16, the popular 16bit computer in the 0x10c universe (2012)
  • Roland, shipboard AI of the UNSC ship Infinity in the Halo franchise first appearing in Halo 4 (2012)
  • M.I.K.E. (Memetic Installation Keeper Engine), from Etrian Odyssey Untold: The Millennium Girl (2013)
  • ctOS (central Operating System), a mainframe computer in Watch Dogs that the player is capable of hacking into (2014)
  • ctOS 2.0, an updated version of ctOS used to manage the city of San Francisco in the game Watch dogs 2 (2016)
  • Rasputin, An AI "warmind" created for the purpose of defending the Earth from any hostile threats in the video game Destiny (2014)
  • Ghost, the AI interface that, through its link with the planet-sized Traveler, resurrects Guardians, also from the video game Destiny (2014)
  • XANADU, a simulation computer composed of many smaller computers, stored in a cavern in Act III of the video game Kentucky Route Zero (2014)
  • TIS-100 (Tessellated Intelligence System), a fictional mysterious computer from the early 1980s that carries cryptic messages from unknown author, from the game TIS-100 (2015)
  • Governor Sloan, AI in control of the independent colony of Meridian in Halo 5: Guardians (2015)
  • 031 Exuberant Witness, Forerunner AI in charge of the Genesis installation Halo 5: Guardians (2015)
  • Kaizen-85, the Nautilus′ main AI that runs a cruise spaceship that is devoid of its human crew, from the game Event[0] (2016)
  • MS-Alice, an AI computer who was created by Marco in Metal Slug Attack (2016)
  • VEGA, an artificial intelligence found in Doom (2016).
  • Athena, the artificial intelligence used to announce locations in Overwatch (2016), and an announcer in Heroes of the Storm (2015)
  • SAM, short for Simulated Adaptive Matrix. An AI created by Alec Ryder in Mass Effect: Andromeda (2017)
  • GAIA, a powerful and supremely advanced A.I. that used a suite of nine subordinate functions to oversee Project Zero Dawn's successful restoration of life to Earth after its eradication by the Faro Plague in Horizon Zero Dawn (2017)
  • SAM (Systems Administration and Maintenance), the AI of the titular space station in Observation (2019).
  • Tacputer, a non-sentient military computer, and HR Computer, a seemingly non-sentient Human Resources computer, in Void Bastards (2019).


  • Queen (Serial Number Q5U4EX7YY2E9N), a computer in a public library transformed into a sentient being by a Dark Fountain in Deltarune Chapter 2 (2021)

Board games and role-playing games[edit]

  • A.R.C.H.I.E. Three, the supercomputer that arose from the ashes of nuclear war to become a major player in the events of Palladium Books' Rifts
  • The Autochthon, the extradimensional AI which secretly control Iteration X, in White Wolf Publishing's Mage: The Ascension
  • The Computer, from West End Games' Paranoia role-playing game
  • Crime Computer, from the Milton BradleyManhunter board game
  • Deus, the malevolent AI built by Renraku from Shadowrun role-playing game who took over the Renraku Arcology before escaping into the Matrix
  • Mirage, the oldest AI from Shadowrun, built to assist the US military in combating the original Crash Virus in 2029
  • Megara, a sophisticated program built by Renraku in Shadowrun, who achieved sentience after falling in love with a hacker
  • Omega Virus, microscopic nano-phages that build a singular intelligence (foreign AI) in the Battlestat1 computer core and take over the space station in the board game by Milton Bradley
  • Zoneminds, a collection of malevolent AIs that have enslaved humanity in the GURPS "Reign of Steel" campaign setting

Unsorted works[edit]

  • SARA, TOM's A.I. matrix companion from Toonami
  • Walter, navigating computer from Amrakus's A Space Rock Opera
  • The CENTRAL SCRUTINIZER, narrator from Frank Zappa's Joe's Garage
  • Ritsu / Autonomous Intelligence Fixed Artillery, from Assassination Classroom
  • Tandy 400, Compy 386, Lappy 486, Compé, and Lappier, Strong Bad's computers in Homestar Runner (Tandy is a real company, but never produced a 400 model)
  • Hyper Hegel, an extremely slow computer run with burning wood in monochrom's Soviet Unterzoegersdorf universe
  • A.J.G.L.U. 2000 (Archie Joke Generating Laugh Unit), a running-gag from the Comics Curmudgeon, depicting a computer who does not quite understand human humor, but nonetheless is employed to write the jokes for the Archie Comics strip
  • Li’l Hal (colloquially known as the Auto-Responder or simply AR), a teen boy's sarcastic brain-clone-turned-sentient-chatbot that lives inside a pair of pointy anime sunglasses in Homestuck.
  • CADIE (Cognitive Autoheuristic Distributed-Intelligence Entity), from Google's 2009 April Fools Story[22]

Computers as robots[edit]

  • Norman, the "CPU" of all the robots in the Star Trek (TOS) episode "I, Mudd"

Also see the List of fictional robots and androids for all fictional computers which are described as existing in a mobile or humanlike form.

See also[edit]

Further reading[edit]


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Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

Christian K. Roberts,1,*Andrea L. Hevener,2 and R. James Barnard3

Christian K. Roberts

1Exercise and Metabolic Disease Research Laboratory, Translational Sciences Section, School of Nursing, University of California at Los Angeles, Los Angeles, California

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Andrea L. Hevener

2Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

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R. James Barnard

3Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, California

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Author informationCopyright and License informationDisclaimer

1Exercise and Metabolic Disease Research Laboratory, Translational Sciences Section, School of Nursing, University of California at Los Angeles, Los Angeles, California

2Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

3Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, California

*Correspondence to ude.alcu@streborc

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The publisher's final edited version of this article is available at Compr Physiol

See other articles in PMC that cite the published article.


Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity.


One earliest references to metabolic syndrome (MS) can be traced back to Camus in 1966 (97). However, in 1988 Gerald Reaven gave the Banting Lecture at the American Diabetes Association national meeting and introduced the concept of what he called “Syndrome X,” an aggregation of independent, coronary heart disease (CHD) risk factors in the same individual. The risk factors included in the syndrome were insulin resistance, defined as the inability of insulin to optimally stimulate the transport of glucose into the body’s cell (hyperinsulinemia or impared glucose tolerance) (note: for purposes of this review, we will use the terms insulin resistance and insulin sensitivity interchangeably), hypertension, hypertriglyceridemia, and low, high-density lipotrotein cholesterol (HDL) (522). The following year Kaplan (333) called it “the deadly quartet” and Foster (205) described it as “a secret killer.” None of these acronyms described the point made by Reaven in his Banting Lecture that insulin resistance/hyperinsulinemia might be the underlying cause of the syndrome. Reaven also suggested that insulin resistance/hyperinsulinemia was an underlying risk factor for T2D, which, at the time, was referred to as noninsulin-dependent diabetes mellitus. In 1991, Ferrannini et al. (194) published an article entitled “Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome,” terms that better reflected Reaven’s point of view. Furthermore, use of the term MS acknowledges that this array of factors is associated with abnormal carbohydrate and lipid metabolism. These authors emphasized that insulin resistance was the underlying factor and, once acquired, those with a genetic predisposition would develop all the other aspects of the disorder. However, Ferrannini et al. pointed out that dietary intake and exercise could reduce insulin resistance, suggesting that the final phenotypic expression involves both genetic and acquired influences. Additionally, Haffner et al. (249) coined the term “insulin resistance syndrome” for the disorder to highlight the fact that insulin resistance preceded other aspects of the syndrome. Some individuals still use the term insulin resistance syndrome but now the term “metabolic syndrome” is more commonly used to describe the aggregation of multiple CHD and T2D risk factors. Insulin sensitivity/resistance is closely related to MS and the major manifestation of MS is coronary artery disease (CAD). In the Insulin Resistance Atherosclerosis Study (IRAS), a multi-ethnic cohort with variable glucose tolerance, the two lowest quintiles of insulin sensitivity, as estimated by frequently sampled intravenous glucose tolerance tests (FSIGT), had ORs of 2.4 and 4.7 for CAD compared with the highest quintile (535).

In addition to the factors mentioned by Reaven, Kaplan suggested that upper-body or visceral obesity needs to be considered as part of the syndrome and as a major risk factor for CHD and T2D, independent of overall obesity. Subsequently, many studies confirmed that visceral obesity (553) was correlated with the MS and its individual components, as reviewed by Despres and Lemieux (155, 156). As more studies were conducted, additional CHD risk factors were added to the syndrome. Landin et al. (380) suggested that elevated serum levels of fibrinogen and tissue plasminogen activator inhibitor were related to metabolic factors for CHD. Small dense particles of low-density lipoprotein (LDL) were found to have increased atherogenicity compared to large, less dense particles (604). Subsequently Barakat et al (46) and Reaven et al. (526) reported that small dense LDL particles were associated with insulin resistance, obesity, and T2D. Thus, small dense LDL was added to the list of factors associated with the MS. The combination of elevated serum triglycerides (TG), depressed HDL, and elevated small-dense LDL particles is commonly referred to as dyslipidemia.

Other aspects of atherosclerosis development and myocardial infarction that have been linked with the MS include endothelial dysfunction (663), inflammation (395, 718), and oxidative stress (661). In an animal model of diet-induced MS (50), Reil et al. (528) reported defective bradykinin and acetylcholine-induced relaxation with a normal response to nitroprusside in isolated artery strips. When the animals were switched from the high-fat, sucrose diet back to a low-fat, starch diet for 4 weeks, the endothelium-dependent defects were eliminated. In a recent study of 819 subjects, Suzuki et al. (621) reported that those subjects with the MS (N = 377) had lower flow-mediated dilation, which is a measure of conduit artery endothelial function, compared to that of subjects without MS.

High-sensitivity C-reactive protein (CRP), a marker for systemic inflammation, is commonly used clinically to evaluate risk in primary and secondary prevention of vascular disease (648). Not surprisingly, CRP has been associated with the MS. Obesity is now recognized as a state of chronic, low-grade inflammation and is associated with increased serum markers of inflammation and oxidative stress (196, 345), and MS has been linked with inflammation and oxidative stress (196, 254). However, as pointed out by Despres and Lemieux (155) in their review, not all obese individuals have the MS. In a recent study, Van Guilder et al. (661) studied three groups of subjects: normal weight, obese without MS, and obese with MS. Plasma CRP was significantly elevated in both obese groups compared to the normal weight group but was significantly elevated in the obese with MS compared to obese without MS. Other markers of inflammation including tumor necrosis factor-alpha (TNFα), interleukin (IL)-6 and IL-18 were only elevated in the obese with MS. Ox-LDL was measured as a marker of oxidative stress and was found to be elevated in both obese groups; the obese with MS was significantly higher that the obese without MS. These results suggest that increased oxidative stress and inflammation might be involved in the development of the MS. In addition, inflamed adipose tissue, characterized by increased monocyte infiltration and cytokine production, (24, 300, 563) has recently been associated with MS.

What Causes the Metabolic Syndrome?

When Reaven introduced the concept in 1988, he suggested that insulin resistance/hyperinsulinemia was the underlying cause. His suggestion was based on cross-sectional data showing associations between hyperinsulinemia and the other aspects of the syndrome in patients as well as experimental studies on rodents fed diets high in sucrose or fructose. Support for the role of hyperinsulinemia in the development of the syndrome came in 1992 when Haffner et al. (249) reported 8 years prospective data from 2217 subjects in the San Antonio Heart Study showing that fasting hyperinsulinemia preceded the development of other aspects of the syndrome including hypertension, hypertriglyceridemia, and depressed HDL-C, as well as the development of T2D. After adjusting for baseline obesity and fat distribution, as well as weight gain over the period of observation, significant relationships between insulin and the other factors remained present. Further support for the importance of hyperinsulinemia came from an animal study by Barnard et al. (50). Feeding rodents a high-fat sucrose diet resulted in skeletal muscle insulin resistance and hyperinsulinemia within a few weeks before any change in body fat or abdominal fat cell size. The animals subsequently developed hypertriglyceridemia, enhanced clotting and hypertension, that is, the MS.

Through his Banting Lecture, Reaven suggested some mechanisms to explain how insulin resistance/ hyperinsulinemia might cause the other aspects of the MS. He pointed out that hypertension was associated with elevated levels of plasma catecholamines and suggested enhanced sympathetic nervous system activity as a contributing mechanism. He also cited studies reporting that insulin caused the kidney to promote sodium reabsorption and increase plasma volume. For the increase in TG associated with the syndrome, he cited a study reporting that in perfused rat livers insulin increased very low density lipoprotein (VLDL) TG production. The San Antonio group provided further support for these mechanisms in two subsequent papers (148, 248). They pointed out that although some data had shown that acutely, insulin could be a vasodilator [as reviewed by reference (54)], prolonged insulin resistance and hyperinsulinemia was associated with hypertension and could be due to several mechanisms including an overactive sympathetic nervous system, sodium retention, altered membrane ion transport, and proliferation of vascular smooth muscle cells. They also stated that hyperinsulinemia would increase liver production of VLDL to increase serum TG, while at the same time reduce high-density lipoprotein production and serum HDL-C. These data all support Reaven’s suggestion that insulin resistance/hyperinsulinemia is the primary factor responsible for the MS. Using the insulin/glucose clamp technique, DeFronzo and Ferrannini (148) demonstrated that cellular resistance to insulin action subtends hyperinsulinemia. The important question, however, is what causes the insulin resistance. Reaven suggested that elevated plasma-free fatty acids were involved in the development of insulin resistance, as originally suggested by Randle et al. (518), and presented some experimental data to support his claim (522).

Based on the 1947 observation of Vague (657), women with upper body obesity were far more likely to get heart disease and T2D compared to women with lower body obesity. Kaplan (333), in 1989, suggested that obesity, especially abdominal obesity, was the primary factor that induced hyper-insulinemia and subsequently the MS. Today, a well-accepted theory on a cause of insulin resistance and the MS is excess abdominal fat. Many studies using waist-to-hip ratio, computed tomography, or similar measures have shown that abdominal fat, especially visceral fat, correlates best with the MS and CHD risk (155). In 1990, Bjorntrop (69) proposed that abdominal or “portal adipose tissue” would release excess free fatty acid that would go directly to the liver, increasing TG formation while also suppressing insulin clearance, resulting in hyperinsulinemia. He further stated that the lipid mobilizing capacity of portal adipose tissue is pronounced in men and abdominally obese women because of an abundance of β-adrenergic receptors with little α-adrenergic inhibition. In their review, Despres and Lemieux (155) discuss other factors associated with abdominal obesity that might be involved in the MS, including increased inflammatory cytokine production by fat cells along with reduced adiponectin release. However, they point out that while an abundance of data show that excess visceral fat is associated with both atherogenic and diabetogenic risk factors, an important question is whether visceral fat is a causal factor or simply a marker for the MS. The prospective studies discussed earlier suggest that it is a marker as opposed to being the true underlying cause.

In an editorial, Landsberg (381) stated, “the most important environmental cause of insulin resistance is central obesity, but a list would also include sedentary lifestyle and high-fat intake.” We would reverse the order to state that the most important cause of insulin resistance is a high-fat, refined-carbohydrate diet and physical inactivity, which are exacerbated by genetic predispositions, such as the development of abdominal obesity, as was suggested in a review by Barnard and Wen published in 1994 (51). Two early studies from the Reaven group reported that feeding rodents diets high in sucrose or fructose resulted in insulin resistance and hyperinsulinemia in as little as two weeks while on the diets (527, 722). A series of studies from the Barnard laboratory (49, 50, 52, 53, 237, 238, 543, 715) demonstrated that when rodents were placed on a high-fat and/or refined-carbohydrate diet compared to a low-fat, starch diet, skeletal muscle insulin resistance with elevated serum insulin developed in a few weeks, prior to differences in body weight or body fat. The high-fat, refined-carbohydrate diet eventually led to hypertension, hypertriglyceridemia, and enhanced clotting as well as obesity, which are characteristics of the MS (49, 50). The observation of diet-induced skeletal muscle insulin resistance is significant, as skeletal muscle is the most important target tissue for insulin action, is the primary site for glucose disposal following a meal (147), and shows a major defect in insulin-resistant T2D patients (147). The diet-induced insulin resistance in the rodent model was associated with a decrease in insulin receptor autophosphorylation and tyrosine kinase activity similar to the defects observed in muscle from type 2 diabetic patients (53, 575, 714). The mechanisms underlying these and other defects that lead to insulin resistance are discussed in detail later.

Clinical Aspects of the Metabolic Syndrome

Since Reaven introduced the concept in 1988, thousands of papers related to MS have been published. A search of PubMed in August 2010 resulted in over 31,000 responses demonstrating a high level of interest in the concept and in 2006 The Journal of the CardioMetabolic Syndrome appeared. The reason for such interest is not surprising as Ford et al. (201, 202) have estimated that using the revised National Cholesterol Education Program (NCEP)/Adult Treatment Panel (ATP) III criteria (182, 240, 241) showed that between 32% and 34% all US adults (31–34% of men and 33–35% of women) have MS. Based on International Diabetes Federation (IDF) criteria, estimates were 39%, with 40% of men and 38% of women (201); similar classification occurred 93% of the time for the two definitions. This equates to greater than 100 million in the US based on a population estimate of 310 million. A multiethnic representative US sample of 12,363 men and women 20 years and older from the third National Health and Nutrition Examination Survey (NHANES) were evaluated for MS as defined by the ATP III diagnostic criteria (abdominal obesity, hypertriglyceridemia, low HDL, hypertension, and fasting hyperglycemia) and the disorder was found to be present in 22.8% and 22.6% of the men and women, respectively. MS was present in 4.6%, 22.4%, and 59.6% of normal-weight, overweight, and obese men, respectively, and physical inactivity was associated with an increased risk of developing the syndrome (488). When Reaven published his paper in 1988 he stated,

“[B]ased on available data, it is possible to suggest that there is a series of related variables – Syndrome X – that tend to occur in the same individual and may be of enormous importance in the genesis of coronary artery disease (CAD)” (522).

Many studies have investigated the syndrome as a possible independent risk factor for CHD. In a 2007 meta-analysis of longitudinal studies involving 172,573 individuals, Gami et al. (219) reported that the relative risk (RR) for individuals with the MS compared to those without the MS was 1.78 for cardiovascular events and death; for women the RR was 2.63. After adjusting for traditional cardiovascular risk factors those with the MS still had a RR of 1.54 for cardiovascular events and death. In 2006, results from another meta-analysis conducted by Galassi et al. (217) showed that the MS was associated with increased incidence of cardiovascular disease (CVD) (RR 1.53), CHD (RR 1.52), and stroke (RR 1.76). Individuals with the MS had increased all-cause mortality (RR 1.35) and cardiovascular mortality (RR 1.74). Again, the risks were higher in women compared to men.

In his 1988 paper, Reaven pointed out that resistance to insulin-stimulated glucose uptake was present not only in patients with T2D but also in a majority of individuals with impaired glucose tolerance (IGT) as well as those with the MS. Thus, it was speculated that individuals with the MS and insulin resistance might be at high risk for the development of T2D; this turned out to be the case. In a meta-analysis of 16 cohort studies, Ford et al. (204) reported that the RR for T2D in individuals with the MS ranged from 4.42 to 5.17 depending on the criteria used to define the MS. The authors concluded that the MS, however defined, has a stronger association with T2D than previously demonstrated for CHD.

Although the MS appears to be a well-accepted syndrome associated with increased risk for both CHD and T2D, the use of the term MS has been questioned for a variety of reasons (326, 523, 525). These include, but are not limited to: (i) it occurs only in insulin-resistant persons, which the ATP III criteria does not directly evaluate and, currently, there is no simple clinical measure for insulin resistance; (ii) many individuals may not satisfy the arbitrary cutoffs for diagnosis, that is, might be sufficiently insulin resistant and have additional CAD risk factors to be at significant increased CVD risk; and (iii) it has low clinical utility since treating the individual factors may be a less effective approach than addressing the underlying problem, which is generally lifestyle-induced insulin resistance in genetically susceptible individuals. In fact, published data support this contention (398).

In 2005, a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes questioned the existence of the MS (326). The groups undertook a review of the literature and concluded:

“While there is no question that certain CVD risk factors are prone to cluster, we found that the MS has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a ’syndrome.”’

The fact that the MS is imprecisely defined stems from the different definitions adopted by different organizations to identify individuals with the syndrome. Due to the fact that insulin resistance is rarely measured clinically, other criteria have been adopted to identify individuals who might be insulin resistant and possess the MS. To date at least six different definitions from five different agencies have been proposed to define adults with the MS, with the criteria being dramatically varied among agencies. The problem is more pronounced in the pediatric arena where, according to Morrison et al. (453), as many as 40 different definitions have been used to identify youth with the MS. This is important as, not surprisingly, pediatric MS predicts adult MS, although in this cohort, body mass index (BMI) risk estimates were similar (415).

In 1998, a consultation group from the World Health Organization (WHO) published the first clinical criterion to define adults with MS (18). These criteria were proposed in part as simple tools to help health professionals identify individuals likely to have a clustering of metabolic abnormalities. Following Reaven’s suggestion, this group emphasized the importance of insulin resistance and suggested several clinical measures that could be used to assess insulin resistance, that is, IGT, impaired fasting glucose (IFG), T2D mellitus, or impaired glucose disposal demonstrated with the insulin clamp test. In addition to a measure of insulin resistance to qualify for the MS, individuals must possess two of the following risk factors: obesity, hypertension, high TG, reduced HDL-C, or macroalbuminuria.

In 1999, the European Group for the Study of Insulin Resistance (EGIR) proposed a slight modification from what had been proposed by the WHO (41). This group used the term insulin resistance syndrome as opposed to the MS. In addition, they suggested also requiring evidence of insulin resistance, as measured by plasma insulin above the upper quartile for the population plus two other factors for the diagnosis, that is, abdominal obesity, hypertension, elevated TG, reduced HDL-C, or elevated plasma glucose. Interestingly, this group excluded T2D as a criterion.

In 2001, the NCEP/ATP III introduced alternative clinical criteria to Reaven’s initially proposed definition to diagnose the syndrome and did not require any measure of insulin resistance, but did require three of the following five criteria, that is, elevated fasting glucose or a diagnosis of T2D, abdominal obesity, elevated blood pressure, elevated TG, or reduced HDL-C (1). Like the EGIR, the ATP III emphasized the importance of abdominal obesity and noted that some ethnic groups show signs of insulin resistance at lower levels of waist circumference than used as criteria for diagnosis of the syndrome.

In 2003, the American Association of Clinical Endocrinologists (AACE) also used the term insulin resistance syndrome and provided their criteria for the diagnosis including IGT or IFG with no specific number of other factors required but the left the decision to be based upon the judgment of the clinician. The major additional criteria to be considered included elevated TG, elevated blood pressure, reduced HDL-C and obesity (BMI). Other factors that could be used in the judgment included family history of atherosclerotic vascular disease or T2D, polycystic ovary syndrome, and hyperglycemia. The presence of T2D was excluded.

In 2005, the IDF (303) provided their criteria to define the MS. Although some of the members of the IDF writing group were also on the WHO consultation group, they replaced the requirement for a direct measure of insulin resistance with emphasis on abdominal obesity as it correlates well with insulin resistance. When abdominal obesity is present, two additional factors listed in the ATP III criteria were sufficient to define the syndrome. The definition of abdominal obesity involved waist circumference that was adjusted for different ethnic groups. For people of European origin (Europeans and Americans) thresholds were set at 94 cm or more for men and 80 cm or more for women. For Asian populations, excluding Japanese, the thresholds were set at 90 cm or more for men and 80 cm or more for women; while the thresholds for Japanese were set at 85 cm or more for men and 90 cm or more for women. The other difference from the ATP III criteria was a lower IFG value (100 mg/dL). This same value was also adopted by the ATP III group in 2005 (ATP III-R) (241). In addition, the lower fasting glucose, ATP III-R added the presence of drug treatment for TG, reduced HDL-C, hypertension, or elevated glucose as additional criteria. The precise cut values for the various criteria used by the different agencies have been outlined in the article describing ATP III-R criteria by Grundy et al. (241).

Thus, one would have to agree with the statement from the two diabetes groups, “ . . . the MS has been imprecisely defined . . .” (326). This lack of precision in defining the syndrome has led to different results in different studies depending on the criteria used to define the syndrome. Katzmarzyk et al. (339) conducted a longitudinal study of 20,789 US men aged 20 to 83 years who were followed for 11.4 years. They identified men with the MS using three different methods, the original ATP III, ATP III-R, and IDF. It was found that at baseline the percentage of men with the MS was 19.7, 27, and 30, according to the different criteria. The RR for cardiovascular mortality for men with the MS was 1.79, 1.67, and 1.67 according to ATP III, ATP III-R, and IDF, respectively; however, there were only 213 cardiovascular deaths total. In a similar study, Benetos et al. (59) followed 84,730 French men and women 40 years or more of age for 4.7 years. They also used three different methods to identify the MS, ATP III, IDF, and ATP III-R. The percent of individuals identified as having the MS were 9.6, 21.6, and 16.5. The RR for cardiovascular mortality was 2.05, 1.77, or 1.64 for the ATP III, ATP III-R, and IDF, respectively; again, the total number of cardiovascular deaths was small (104) over the 4.7 years. The results from these two studies on large populations clearly show that the different criteria used by the different agencies to define individuals with the MS varies dramatically, by as much as 50%. Regardless of the criteria used to identify the MS, both studies showed that the presence of the MS by any of three different definitions increased the risk for cardiovascular mortality but also with significant variability in risk.

Although the data clearly show that the presence of the MS increases the risk for CVD and cardiovascular mortality, some have questioned whether there is a need to identify such patients, especially since: (i) MS may not predict cardiovascular events better than the sum of its components and (ii) none of the definitions include traditional, well-established cardiovascular risk factors, such as smoking, total or LDL cholesterol and age factors that are standard clinical measures, along with blood pressure and HDL-C that are incorporated into the Framingham Risk Score (FRS). Wannamethee et al. (677) reported a prospective study of 5128 British men with no initial history of CHD or T2D, followed for 20 years. They compared the FRS with the MS identified by ATP III-R criteria as predictors for CHD, stroke, or T2D. Using ATP III-R criteria for MS the RR for CHD was 1.64, for stroke was 1.61 and for T2D was 3.57. When they compared the MS with the FRS, they found that the FRS was superior to the MS in predicting CHD and stroke but found it to be inferior in predicting T2D. de Zeeuw and Bakker (146) conducted a similar study of 8217 Dutch men and women followed for a median 6.5 years. The results showed that the FRS was superior to the MS in predicting cardiovascular mortality/morbidity. The FRS appears to be superior in identifying CHD risk not only because it contains the well-established CHD risk factors not included in the MS, but also because it is based on continuous data, as opposed to the discrete cutoff points used to identify the MS. Even Reaven (524) criticized the ATP III criteria, stating that the cut points are arbitrary and not based on sound scientific data, while insulin sensitivity is continuous in normal populations with at least a sixfold variation between the most sensitive and the most insulin-resistant individuals. Thus, he states that there is no simple, objective way to classify an individual as being insulin resistant, which he claimed was the basis for his syndrome X.

Despite the criticisms, the MS has been strongly defended, especially since it is a powerful predictor for T2D [80% of those with T2D have MS (309)] and a major risk factor for CHD (233, 309). For example, in a cohort of 3323 middle-aged adults, the MS RR was 2.88 for CVD, 2.54 for CHD, and 6.92 for T2D in men and 2.25, 1.54, and 6.90 in women, respectively (695). Sattar et al. (571) noted that men with four or five features of the syndrome have been estimated to have a 3.7-fold increase in risk for CAD and a 24-fold increased risk for T2D compared with men with none, while Klein et al. (358) reported 2.5% and 1.1% incidence of CVD and T2D, respectively, in those with one component of the MS; meanwhile 15% and 18% developed these diseases in those with four or more components of the syndrome.

MS is also a predictor of mortality. For example Lakka et al. (377) reported that middle-aged men with the MS exhibited a 2.9- to 4.2-fold risk of CHD death over an 11-year follow-up compared to healthy men and after adjustment for conventional risk factors. In addition, all-cause mortality was increased 2.3-fold in those in the highest quartile for MS factors. In the Botnia study of 4483 subjects from Finland and Sweden, Isomaa et al. (309) estimated the risk for cardiovascular mortality over a 7-year follow-up was increased markedly in those with MS (12.0% vs. 2.2%). A meta-analysis noted increased risks of CVD [odds ratio (OR): 2.40] and all-cause (OR: 1.58) mortality in subjects with MS (454).

Grundy (239) stated that the intended definition of the MS was not a tool to estimate absolute risk, but rather a tool to be used by clinicians to improve obesity counseling. In an attempt to clear up some of the controversy and unify the clinical definitions of the MS, a meeting was convened with representatives from the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. In 2009, a “joint interim statement” was published in Circulation (17), attempting to establish criteria to identify patients with the MS as shown in Table 1. It was agreed that there should not be an obligatory component, although there was agreement regarding the importance of central obesity, and thus waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of five would qualify a person for MS. A single set of cut points would be used for all components except waist circumference, for which further work is required, and, at present, would be based upon population/country-specific definitions. The statement reiterated that patients with MS have two and five times the risk of developing CVD and T2D, respectively, over the next 5 to 10 years, as compared to individuals without MS.

Table 1

Established Criteria Proposed for Clinical Diagnosis of Metabolic Syndrome

Clinical measureWHO (1998)IDF (2005)Joint IDR/NHLBI/AHA
Insulin resistanceIGT, IFT, T2DM, or lowered insulin sensitivity*
Plus any two of the following
But any three of the following five features
Body metricMen: waist-to-hip ratio >0.90
Women: waist-to-hip ratio >0.85 and/or BMI >30kg/m2
Increased WC (population specific) plus any two of the followingPopulation- and country-specific definitions
LipidTG 150 mg/dL and/or HDL-C <35 mg/dL in men or <39 mg/dL in womenTG > 150 mg/dL or on TG Rx≥150 mg/dL (1.7 mmol/L)

HDL-C <40 mg/dL in men or <50 mg/dL in women or on HDL-C Rx<40 mg/dL (1.0 mmol/L) in males; <50 mg/dL (1.3 mmol/L) in females
Blood pressure≥140/90 mmHg≥130 mmHg systolic or 85 mmHg diastolic or on hypertension RxSystolic ≥130 and/or diastolic ≥85 mmHg
GlucoseIGT, IFG, or T2DM≥100 mg/dL (includes diabetes)≥100 mg/dL

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As the debate continues more and more data are published relating insulin resistance and/or the MS to other common health problems found in the industrialized nations. In 2006, the Harvard School of Nutrition hosted a conference, Metabolic Syndrome and the Onset of Cancer, where several papers were presented showing that hyperinsulinemia was related to breast, prostate, and colon cancers. The proceedings were published in September 2007 in a supplement to the American Journal of Clinical Nutrition. Barnard (48) suggested that the MS was linked to prostate cancer risk as a result of hyperinsulinemia acting on the liver to increase production of insulin-like growth factor-I (IGF-I), a factor known to stimulate tumor growth and block apoptosis. Kalmijn et al. (327) reported that men diagnosed with the MS in their early 50s were more likely to develop dementia, especially vascular-related dementia, later in life. In a recent review, Galluzzo et al. (218) pointed out that several recent studies recommend that women with polycystic ovary syndrome should be evaluated for MS and that lifestyle modification should be the first-line therapy. Kawamoto et al. (343) tested over 3000 men and women and reported that those with the MS had a risk ratio of 1.53 for chronic kidney disease. Tsochatzis et al. (649) reported that insulin resistance was associated with chronic liver disease, especially hepatitis C and nonalcoholic fatty liver disease (449), and MS predicts hepatic steatosis (252). Additionally, accumulating evidence supports that sleep apnea is a manifestation associated with MS (665). D’Aiuto et al. (139) analyzed data from 13,994 men and women from the Third National Health and Nutrition Examination Survey (NHANES) and found that individuals with severe periodontitis were 2.31 times more likely to have the MS compared to individuals without periodontitis. D’Aiuto et al. (139) even suggested that the chronic low-grade inflammation characteristic of periodontitis might contribute to the development of the MS. The mechanisms linking the MS to CHD and T2D are well understood; however, the links to these other health problems are not well understood and require further study.

It is obvious that much more research is needed before we understand how all of these factors are related from a mechanistic point of view. It is also likely that the true underlying factors are inappropropriate diet and physical inactivity, characteristic of industrialized nations. In an analysis of the 1999–2004 NHANES data, Wildman et al. (693), showed support for the value of physical activity in preventing the MS. They found that 23.5% of normal weight (BMI < 25) were metabolically abnormal while 51.3% and 31.7% of overweight or obese (BMI > 30) were metabolically healthy. Low physical activity was an independent correlate of clustering of cardiometabolic factors in the normal-weight individuals while high physical activity correlated with zero or only one cardiometabolic abnormality in the overweight or obese individuals. The importance of exercise, and to some extent diet, will be discussed in the later sections.

Insulin Action

Section “Overview” will focus on an overview of the molecular aspects of insulin resistance. Insulin resistance (i.e., low insulin sensitivity) has been suggested as the major underpinning link between physical inactivity and MS. Many tissues, including skeletal muscle, liver, and adipose tissue may exhibit insulin resistance. Given the clinical benefit of treating those with insulin resistance, techniques have been developed to assess insulin sensitivity in vivo. The euglycemic-hyperinsulinemic glucose clamp (EHC) involves injecting a fixed dose of insulin to increase insulin to postprandial or to supraphysiological levels with normal glucose concentrations being maintained by infusing glucose. The glucose infusion rate (often referred to as M-value) reflects insulin sensitivity and is generally considered an inverse measure of insulin resistance; glucose disposal is often also determined. The FSIGT can estimate insulin sensitivity and acute insulin response using the Bergman minimal model (65), yielding a hyperbolic relationship between insulin secretion and insulin sensitivity (9). The product of these two indices is referred to as the disposition index (DI), a marker of β-cell function. As depicted in Figure 1, exercise training/physically activity status modify insulin sensitivity and insulin secretion in accordance with this relationship, and failure of insulin secretion to compensate for a fall in insulin sensitivity leads to elevated fasting glucose and prediabetes (impaired glucose tolerance), and depending on genetic predisposition a continued progressive decline in both insulin secretion and insulin sensitivity to T2D. Generally, use of the EHC and FSIGT are the gold standard methods for estimation of insulin sensitivity and/or β-cell function. However, these methods are expensive, not simple to perform and generally not applicable in standard clinical practice. The oral glucose tolerance test (OGTT) is less expensive and its simplicity allows for more widespread use. Other techniques used include insulin suppression testing, insulin tolerance testing (ITT) and continuous glucose monitoring systems (CGMSs).

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Figure 1

Graph depicting the hyperbolic relation between insulin secretion and insulin sensitivity. Insulin secretion rises as insulin sensitivity falls when an individual goes from a state of exercise training/being physically active (point A) to detraining/sedentary (point B) and vice versa, that is, bidirectionality of the two arrows from B to A when undergoing exercise training/increasing physical activity levels. A failure of insulin secretion to compensate for a fall in insulin sensitivity is noted when both insulin secretion and insulin sensitivity decline from points B to C, leading to elevated fasting glucose and prediabetes (impaired glucose tolerance). A progressive decline in both insulin secretion and insulin sensitivity to point D indicates type 2 diabetes. Adapted from reference (9) with permission.


Insulin is a polypeptide hormone that was first discovered in 1921 by Frederick G. Banting and Charles H. Best while working in the laboratory of J.R. Macleod at the University of Toronto. The hormone was later purified in 1923 by James B. Collip and is now used in clinical practice to treat insulin deficiency diseases, including type 1 and T2D. Insulin is secreted from the β-cells of the pancreatic islets of Langerhans in response to glucose and amino acids consumed during a meal. Insulin is a central regulatory hormone in the maintenance of glucose homeostasis and is also involved in anabolic processes including tissue growth and development. In a healthy person, glucose is controlled within very narrow limits in the blood. This is achieved by the regulation of glucose production by the liver, and to a lesser extent the kidney, as well as uptake by peripheral tissues, primarily skeletal muscle, liver, and adipose tissue. In addition to the control of blood glucose, insulin also exerts strong control over lipid metabolism by stimulating lipid synthesis in liver and fat cells and by attenuating lipolysis, that is, TG breakdown to fatty acids.

Glucose is utilized by cells to produce potential energy in the form of adenosine triphosphate (ATP). The entry of glucose into the cell is achieved primarily via a carrier-mediated process, which includes a family of transporters known as GLUT proteins. GLUT, proteins encoded by SLC2A family members, are membrane proteins found in most mammalian cells and contain 12 membrane-spanning helices with both the amino and carboxy terminal regions exposed on the cytoplasmic side of the plasma membrane. To date, over 14 GLUT family members have been identified (317). Each transporter isoform performs a specific role in hexose metabolism as dictated by expression patterns within tissues, protein transport kinetics, substrate specificity and the physiological conditions controlling gene expression. The GLUT family is divided into three subclasses based upon sequence similarities; however for the purposes of this review, we will focus on the well-characterized class I glucose transporters, GLUT1–GLUT4, as these are primarily expressed in glucoregulatory tissues. Insulin-stimulated transport of glucose into cells is achieved by insulin binding to its cell surface receptor and the initiation of a cascade of signaling events culminating in the redistribution of GLUT4 (the insulin responsive glucose transporter) to the plasma membrane. Glucose is then transported across the plasma membrane where it is immediately phosphorylated and either stored as glycogen or metabolized to produce ATP. In the subsequent sections we will provide an overview of the insulin signal transduction pathway and glucose transport system as well as discuss the mechanisms contributing to impaired insulin action, insulin resistance. We will explore both myocyte-related mechanisms contributing to skeletal muscle insulin resistance as well as describe insulin resistance producing factors secreted from adipose tissue and liver. We will close this section discussing the impact of muscle-secreted factors on metabolism and propose that myokines may in part mediate aspects of exercise-induced effects. Much of the focus of this section will be centered on muscle insulin action as exercise-induced improvements in insulin sensitivity appear related to gains in muscle rather than hepatic insulin action (356, 696).

Insulin Signal Transduction

Insulin and the insulin receptor

Insulin is a peptide hormone, consisting of 51 amino acids with a molecular weight of 5808 Da, secreted by the pancreas as either the full length proprotein or as the fully biologically active form in which the c-peptide is cleaved. Because insulin release into the portal circulation is susceptible to first pass degradation by the liver, c-peptide escapes this fate and is therefore a more accurate marker of insulin secretion. Insulin binds to its receptor (IR) in target tissues including skeletal muscle, liver, and adipose tissue. The IR gene is located on chromosome 19 and is comprised of 22 exons and 21 introns, spanning 150 kb (580). IR is synthesized as a preproreceptor. Following cleavage of a 30-aa signal peptide, the proreceptor undergoes glycosylation, folding, and dimerization. The final IR product consists of a heterotetrameric complex of two α-subunits and two β-subunits linked by disulphide bonds (Fig. 2). In glucoregulatory tissues, including adipose and muscle, the IR is thought to be more highly localized to caveolae located in the plasma membrane (247).

The basal form of the insulin receptor has very low kinase activity, as the activation loop, which traverses the N-and C-terminal lobes in the unliganded state, blocks ATP, and substrate binding (295). Insulin, following binding to the extracellular α-subunits, yields a conformational change in the receptor and transmits a signal across the plasma membrane, which activates the intrinsic tyrosine kinase domain of the intracellular β-subunit. This results in a series of intermolecular autophosphorylation reactions on tyrosine residues that are now known to serve distinct functional roles (138, 391).

Comprehensive studies using selective mutations in the IR as well as computational models from crystal structure analyses have yielded specific details regarding these molecular events (296, 727). Specifically, insulin binding causes the phosphorylation of three key tyrosine residues (Y1158, Y1162, and Y1163), allowing for movement in the A-loop and exposure of the ATP and substrate binding sites (178, 296, 551). Additionally, auto-phosphorylation of tyrosine residues 965 and 972 in the juxtamembrane region, 1158, 1162, and 1163 in the regulatory region (also known as the activation loop of the kinase domain), and 1328 and 1334 in the C-terminus of the cytoplasmic domain of the IR are essential for full kinase activity (687). Moreover it was shown that pTyr 960 is critical for appropriate IR substrate recognition (392), and pTyr972 serves as a binding site for the phospotyrosine binding domains (PTB) of IRS-1, Shc, and STAT5 (110, 246, 321, 573) (Fig. 2). Considered an important feature of hormone signaling, the autophosphorylated IR is rapidly internalized following ligand binding. Endocytosis of the IR leads to proteolytic degradation of the ligand receptor complex, thus terminating ligand action. Recent work by Fagerhom et al. (184) shows that this process is caveolae-mediated and involves the tyrosine phosphorylation of caveolin-1.

Proximal insulin signaling

The IR, upon phosphorylation, recruits various substrates and scaffolding proteins to exert downstream effects. These include the four well-described insulin receptor substrate (IRS) proteins, or IRS1–4, as well as Gab1, SIRPs, Cbl, Shc, and APS (Fig. 3) (500, 632). Upon phosphorylation, these substrates serve as docking or scaffolding platforms for distinct cellular kinases or effectors that mediate the divergent biological actions of insulin. In addition, each of these substrates may be compartmentalized to distinct cellular locations also owning to the specificity to which interactions with other proteins or lipids occur and to which unique downstream effects are achieved. For example, IRS and Shc are recruited to the juxtamembrane region in IR containing a critical arginine-proline-any amino acid-tyrosine (NPXY)-binding motif (342, 468), while APS binds directly to the activation loop.

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Figure 3

Schematic of insulin signal transduction through canonical IRS1/PI3K pathway and through abbreviations: Cbl/CAP/TC10 pathway associated with lipid rafts in the plasma membrane. Akt or PKB, protein kinase B; APS, adapter protein with a PH and SH2 domain; CAP, c-Cbl-associated protein; Cbl, protooncogene; GLUT4, insulin responsive glucose transporter highly expressed in myocytes and adipocytes; IRS, insulin receptor substrate; PDK1, phosphoinositide-dependent kinase 1; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PKC, protein kinase C; TC10, small Ras-related GTPase, member of the Rho family.

Insulin receptor substrate-1, 2

IRSs are the major substrates of the insulin receptor and the IGF)-I receptor tyrosine kinases. Of the several IRS proteins described, IRS-1, 2 are shown to have biological relevance in peripheral tissues for glucose transport. Briefly, tyrosine phosphorylation of IRSs creates recognition sites for additional effector molecules containing Src homology 2 (SH2) domains, including the adaptor proteins Grb2 and Nck, the SHP2 protein phosphatases and the 85-kDa, p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) (686). The pleckstrin homology (PH) domain of the substrate protein is obligatory to elicit the full signal response, as insulin-stimulated tyrosine phosphorylation is significantly reduced in by PH deletion (460). Both IRS-1 and IRS-2 contain multiple YXXM motifs that are phosphorylated by the activated IR (687). In vitro, IRS-1 and IRS-2 display similar capacities to bind p85 of PI3Ks. With respect to insulin action and substrate metabolism, critical roles for IRS-1 and IRS-2 are well established (627, 697). Furthermore, human genetic inactivating mutations in either Isr1 or Irs2 are associated with insulin resistance and T2D (47, 427). While the IRS family shares a high degree of homology, studies in genetically engineered rodents delineate specific roles for these protein isoforms (637, 697). Genetic ablation of either Irs1 or Irs2 in rodents or cells leads to dire physiological consequences, including impaired insulin signal transduction and growth retardation (25, 627).


IRS-1 was first identified by Sun et al. in 1991 and was found to be expressed in a wide variety of tissues (619, 620). Irs-1 null mice are growth restricted and display marked skeletal muscle insulin resistance, but the development of frank T2D in this model is prevented by pancreatic Irs2-induced hyper-insulinemic compensation (25, 627). Furthermore, short-term inhibition of Irs-1 by anti-sense oligonucleotide administration in rats recapitulated much of the insulin resistance phenotype observed in Irs-1 knockout mice (26). In the context of findings for Irs-1 deletion relating to insulin action, recent evidence obtained from Irs-1 transgenic mice suggests that increased expression of IRS-1 is not associated with improved insulin sensitivity (455). In fact, transgenic mice displayed glucose intolerance, increased visceral adipose mass, and increased levels of circulating inflammatory cytokines (455). Interestingly, while Irs-1 mRNA was significantly elevated in all tissues, IRS-1 protein levels were preferentially elevated by 50% and 200% in skeletal muscle and adipose tissue, respectively. The IGT seen in the transgenic mice is explained by reduced tyrosine phosphorylation of IR and YXXM motif of IRS-1 in liver, which may be caused by indirect action given that IRS-1 protein levels were unchanged in liver (455). Taken together these data indicate a relatively narrow window in which IRS-1 levels must be maintained to preserve glucose homeostasis and healthy tissue morphology.


IRS-2 is expressed in all of the primary glucoregulatory tissues including pancreas, liver, adipose, and skeletal muscle. Mice with an Irs2 homozygous null mutation display metabolic defects in liver, muscle, adipose, and pancreas but develop frank diabetes as a result of defects in signal transduction in pancreatic β-cells (511, 697). Furthermore, the importance of IRS-2 in regulating β-cells mass and in the prevention of type 1 diabetes was recently shown by Norquay et al. (467) in nonobese diabetic (NOD) mice overexpressing IRS-2 in β-cells. Remarkably, glucose tolerance was markedly improved and the risk of diabetes decreased 50% in NOD Irs2 Tg mice due to a tenfold greater β-cell mass. In contrast to pancreas, IRS-2 is not necessary for insulin or exercise-stimulated glucose transport in skeletal muscle (268). In liver, insulin-stimulated regulation of sterol regulatory element-binding protein (SREBP)-1c and fatty acid homeostasis is previously thought to depend almost exclusively on the IRS-2 arm for activation of PI3K, PDK1, and atypical protein kinase C isoforms (aPKCs) (187, 561, 602). Again, recent work from the laboratory of Morris White using Lox Cre approach to generate mice with hepatic specific deletions of IRS-1 and or IRS-2 calls into question the established role of IRS-2 in the liver. Findings suggest that IRS-1, not IRS-2, plays a dominant role in regulating hepatic nutrient homeostasis (243). Whether these findings in rodents can extend to isoform specific roles in regulating insulin action in human tissues requires further investigation.

Insulin Receptor Downstream Effectors

Phosphoinositide 3,4,5 (PI3)-kinases

It is well accepted that class IA PI3K is required for insulin-dependent GLUT4-mediated glucose transport in muscle and adipose. In mammals, this class of kinase comprises a p110 catalytic subunit (p110 α, β, or δ) bound to one of five “p85” regulatory subunits (p85α, p85β, p55α, p55γ, or p50α). In the relative absence of insulin, p85 is bound tightly and stabilizes basal p110 protein, inhibiting its catalytic lipid kinase activity. In contrast, during insulin stimulation, the p85–p110 complex is recruited to phosphotyrosine residues in activated receptor or adaptor molecules containing SH2 domains. Recruitment of the p-85/p110 heterodimer to a location proximal to the plasma membrane brings p110 into close proximity with its lipid substrates, thus reducing the inhibitory actions of p85 on p110. Class IA wortmannin sensitive PI3K generates phosphatidylinositol 3,4,5 triphosphate, from PIP3 PtdIns (4,5)P2 at the cell surface and this is thought to interact with specific lipid binding domains present in Ser/Thr protein kinases, including PDK1 and protein kinase B (PKB/Akt). Subsequently, these kinases then act upon GTPases and other scaffolding proteins to promote further propagation of the insulin signal. Early studies using wortmannin to inhibit PI3K showed the insulin-mediated glucose transport into cells is nearly abolished; therefore, PI3K is considered a central and essential signaling regulator for a variety of biological cell responses, notably growth, proliferation, and metabolism (222).

Mammals express seven PI species, two of which are described above and the function of five of which remains poorly understood. While PtdIns(3,4,5)P3 is shown to rise transiently in response to acute insulin treatment and is thought to be the primary PI species regulating metabolic processes, overexpression of PtdIns(3,4,5)P3 alone is not sufficient to fully stimulate transport-mediated uptake of glucose into cells (590). Furthermore, a role for class II wortmannin-insensitive PI3K C2α and the other five PI species has recently been proposed for fine tuning the overall metabolic response of a cell to insulin (185, 590). The importance of this adjunct-signaling pathway in glucose disposal and insulin sensitivity requires further investigation.


Protein kinase B, also known as Akt, is a Ser/Thr kinase involved in a large and diverse set of cellular processes including glycolysis, glycogen synthesis, lipogenesis, suppression of gluconeogenesis, and cell survival. One of Akt’s many important functions is mediating the metabolic actions of insulin to stimulate glucose transport (688). Akt is a PI 3-K effector molecule and its isoform expression dictates cell specific actions in vivo. RNA silencing studies conducted by the Czech laboratory (728) and gene deletion strategies in mice conducted by the Birnbaum laboratory (38) show that Akt2/PKBβ is critical for insulin-mediated glucose disposal. While it is well accepted and evident that it serves as an essential role for Akt2 in glucose transport, studies where Akt inhibition did not cause impaired glucose uptake have been reported. While Akt is thought to be a central effector driving glucose transport, other signaling cascades are thought to participate in parallel including the aPKCλ/ζ (187, 188, 363), p-38 mitogen-activated protein kinase (622), and the CAP/c-Cbl/TC10 cascade (57, 500).

Atypical protein kinase C isoforms, PKCλ, ζ

aPKCs are also downstream effectors of PI 3-K; however these signaling molecules may serve different functions in regulating substrate metabolism in the various glucoregulatory tissues (187). In muscle IRS-1 knockout has a marked effect on aPKCs whereas IRS-1 knockout in liver has little effect on aPKC activation (561). While a role for aPKCs in regulating glucose uptake and metabolism is shown in muscles and in the liver, aPKCs are thought to exert insulin-mediated effects preferentially on hepatic lipid synthesis via regulation of SREBP-1c (SREBP-1c) (422). While previously considered an independent and parallel effector signaling system, recent evidence supports that aPKCs and the TC10 pathways may interact at the plasma membrane (111, 331). Atypical PKCs belong to the AGC subfamily of protein kinases [reviewed by Pearce et al. (491)] and, thus, while phosphorylated by PDK1 downstream of PI3K, can be recruited to lipid rafts in a TC10-dependent manner by Par3 (partitioning-defective) and Par6 proteins (331). Thus, atypical PKCs may represent a point of convergence between PI3K signaling and the TC10 pathways (111). Furthermore, evidence from the Klip laboratory shows that PKCε translocates to the plasma membrane of C2C12 myotubes in culture in response to contraction and that GLUT4 translocation proceeds in a PKCε-dependent manner (464). Whether PKCε is critical for glucose transport into muscle during physical exercise remains to be demonstrated.


The Rab-GTPase activating protein known as AS160 (or TBC1D4) is a 160 kDa putative substrate of Akt (330) and is widely expressed in a variety of tissues including brain, testes, kidney, pancreas, liver, heart quadriceps, and white and brown adipocytes. AS160 undergoes phosphorylation in response to insulin and contains multiple Akt phosphorylation sites: Ser318, Ser341, Ser570, Ser588, Thr642, and Ser751 (330, 565). In addition to insulin, AS160 is phosphorylated in response to PDGF, activation of nPKCs and adenosine monophosphate kinase (AMPK), and following skeletal muscle contraction (216, 639). AS160 is thought to regulate GLUT4 trafficking as well as serve as a convergence point for insulin and contraction-mediated GLUT4 translocation to the plasma membrane (334, 366). Briefly, GLUT4 vesicles migrate and recycle along the cellular framework of cytoskeletal elements and are acted upon by molecular chaperone and GTP-bound Rab proteins. Insulin stimulation causes a rapid phosphorylation of AS160 and its dissociation from GLUT4 vesicles. Removal of AS160 from the vesicle causes an accelerated rate of GLUT4 exocytosis, leading to greater accumulation at the plasma membrane culminating in elevated cellular glucose uptake (723). Phosphorylation incapable AS160 abolished insulin, PDGF, K+ depolarization, and AICAR-induced GLUT4 translocation (639). Furthermore, Karlsson et al. (334) have shown that insulin-stimulated phosporylation of AS160 is significantly impaired in type 2 diabetic muscle. More recently, TBC1D1, an AS160 paralog was identified by immunoprecipitation and mass spectral analyses (635), and its expression is several-fold higher in skeletal muscle versus other insulin responsive, glucoregulatory tissues. Similar to TBC1D4 (AS160), TBC1D1 is phsophorylated in response to insulin, exercise, and AMPK activation by AICAR; however, many novel AMPK binding sites have been identified and activation studies reveal AMPK as a more robust regulator of this signaling molecule (635, 643). Furthermore, genome wide association across multiple strains of mice identified TBC1D1 as an important obesity and diabetes candidate gene (109), similar linkage was established in human subjects as well (616). Mice harboring a truncated TBC1D1 protein lacking the Rab-GTPase-activating protein domain conferred a lean phenotype despite consumption of a high-fat diet (109). These engineered mice showed impaired glucose metabolism and thus relied more heavily on fatty acids as a primary fuel source as reflected by the reduced respiratory quotient and increased rates of whole body fatty acid oxidation, a finding recapitulated in C2C12 myotubes.

Insulin signaling via PI3-kinase independent pathway: CAP, c-Cbl, and TC10

Given the evidence that PI 3-K activation alone is not fully sufficient to achieve insulin-mediated glucose transport, activation of one or more class I PI3K-independent pathways is thought to be requisite (564, 681). This alternative signaling hypothesis is also supported by the fact that glucose transport is stimulated by exercise and hypoxia, independent of any detectable alteration in PI3K. TC10, identified by Chiang et al. (115), along with the canonical PI3K pathway are thought to be required to achieve the full effects of insulin to stimulate GLUT4 translocation. TC10 is a Rho-like GTPase that is highly expressed in adipocytes and skeletal muscle (115). Activation of PI3K-C2α (wortmannin insensitive) is also proposed to occur via TC-10 (111,185). TC-10 dependent actions were found to rely on localization to caveolin-enriched lipid raft microdomains (564, 681).

Within these lipid domains resides the Cbl protooncogene and its adaptor proteins, CAP (Cbl-associated protein) and APS (Cbl-binding protein). Insulin acting through its receptor stimulates the phosphorylation of APS and then Cbl on tyrosine residues (403, 564). Phosphorylated Cbl binds to CAP and migrates to the caveolin-enriched lipid rafts where the CAP complex is anchored by the lipid raft-associated protein flotillin (403, 564). Subsequently, the Crk/C3G (a guanyl nucleotide exchange factor) complex is recruited to this microdomain, leading to the activation of TC10. In that much of this work was performed in adipocytes, findings from JeBailey et al. (314) suggest that TC10-dependent signaling may function differently within other cell types. Additional studies are required to parse out the tissue specific function of the CAP/c-Cbl/TC10 pathway in the regulation of glucose disposal in vivo.

GLUT4 expression

Adipose tissue and skeletal muscle are primary sites of postprandial glucose uptake, and GLUT4, the primary insulin responsive glucose transporter, is highly expressed in these tissues. Under fasting conditions, when circulating insulin levels are low, GLUT4 is minimally present at the plasma membrane and is instead sequestered to intracellular membrane compartments (680). Consumption of a meal stimulates insulin secretion from the pancreatic β-cells and activates a cascade of events as mentioned above that culminate in the movement of the GLUT4 vesicle to the plasma membrane thus increasing transport of glucose from the blood into the cell to participate in metabolism or storage as glycogen. The mechanisms and cellular machinery involved in GLUT4 packaging and trafficking are reviewed in detail elsewhere (89, 167, 332, 348, 383, 402, 443, 444, 501, 680). Suffice to say, an essential role for GLUT4 in insulin-mediated glucose transport is well established.

GLUT4 null mice show many severe developmental defects and a shortened life span (84, 336). Mice heterozygous for the null mutation were insulin resistant and predisposed to diabetes (336, 609). Ablation of GLUT4 specifically in skeletal muscle led to glucose intolerance and severe impairments in insulin-mediated glucose disposal into muscle in mice as young as 8 weeks of age (730). Ablation of GLUT4, specifically in adipose tissue, led to secondary phenotypes of insulin resistance in skeletal muscle and liver, suggesting that an impairment in glucose transport in adipose causes the release of a secretory factor that impairs insulin action in other glucoregulatory tissues (5). Clearly, expression of GLUT4 in skeletal muscle and adipose tissue is essential for the maintenance of glucose homeostasis; however, defects in GLUT4 expression cannot explain the insulin resistance associated with obesity and T2D in rodents or humans (45, 83, 220, 221). Despite this, genetic overexpression or exercise-induced elevation in GLUT4 expression can ameliorate insulin resistance observed in diabetic and obese rodents and humans (84, 255, 531).

Mechanisms of Insulin Resistance

Resistance to the biological effects of insulin is a hallmark feature of the MS and an important contributing factor in the pathogenesis of T2D. In the early stages of insulin resistance, the pancreas compensates by increasing the secretion of insulin into the bloodstream in an attempt to overcome defects in peripheral insulin action. In response to this increased demand for insulin production, the β-cells hypertrophy. Under fasting conditions, basal compensation is sufficient to maintain blood glucose in the normal range. Following a meal though, when glucose is rapidly absorbed from the gut, a relative lack of insulin due to inadequate compensation is detected as the glucose excursion over time is exaggerated. This inability to take up and dispose of glucose appropriately following a meal or glucose challenge is known as glucose intolerance.

It is important to note that genetic mutations or defects in the participants of the insulin-signaling cascade only in rare occasions underlie the insulin resistance and T2D. It is now well supported that lipid oversupply and alterations in substrate metabolism due to inactivity are central underpinnings of chronic tissue inflammation and contribute to the manifestation of peripheral insulin resistance. Tissue accumulation of bioactive lipid species in peripheral tissues activate proinflammatory signaling pathways and novel PKCs; and as reviewed in references (576, 651), which are shown to impair insulin signal transduction by altering key phosphorylation events and key protein-protein interactions. Postreceptor defects are thought to account for much, if not all, of the impairment in muscle insulin action observed in T2D. Many agree that impaired insulin action at the level of IRS-1 occurs as a result of stress kinase activation [e.g., c-Jun N-terminal kinase (JNK) and nuclear factor-κB (IκB) kinase (IKK)β] and impaired phosphorylation of IRS-1 (10, 11, 555). Reduced IRS-1 phosphorylation on critical tyrosine residues and prevents binding with p85 of PI3K and downstream signal transduction. Furthermore, alteration in phosphorylation status, specifically phosphorylation of serine residues, is shown to target IRS-1 for proteasomal degradation and this is a plausible explanation for reduced IRS-1 protein levels in glucoregulatory tissues harvested from obese and/or diabetic rodent (13, 495, 510, 674). Recent work from Shulman, Copps et al. calls into question this paradigm, as in vivo evidence in mice suggests that phosphorylation of IRS-1 at Serine 307 (human Ser312) may promote insulin sensitivity (130). Given conflicting findings to previous studies from the same investigators, further studies will be necessary to test whether selective phosphorylation of IRS-1 on specific serine/threonine residues can modulate insulin action in glucoregulatory tissues in human subjects.

Downstream of IRS-1, PI3K exists in a heterodimer composed of a p110 catalytic subunit and a p85 regulatory subunit as described above. Transcription of the Pik3r1 gene leads to expression of three splice variants p85α, p50α, and p55α (213) and when under normal conditions are in excess compared to the expression of the p110 catalytic subunit. All three variants can bind p110. Interestingly, all three variants are elevated in total in skeletal muscle samples from obese and type 2 diabetic subjects; this increase in expression is associated with reduced insulin resistance and diminished insulin-stimulated PI3K activity (43). Findings in mice with a heterozygous deletion of p85 splice variants as well as in mice with a homozygous deletion of p85α or p85β support the notion that while p85 is critical in recruiting the catalytic subunit of PI3K to IRS proteins, excess levels of monomeric p85 play a role in the inhibition of insulin signaling (425,655).

Lipid phosphatases—SHIP and PTEN

PI3-kinase activity is attenuated by dephosphorylation via 3′ and 5′ lipid phosphatases. SH2 domain containing inositol 5′phosphatase 2 (SHIP2) and skeletal muscle and kidney-enriched inositol phosphatase (SKIP) hydrolyze PI(3,4,5)P3 to PI(3,4)P2, while the phosphatase and tensin homolog deleted on chromosome ten (PTEN) hydrolyzes PI(3,4,5)P3 to PI(4,54)P2. SHIP2, as opposed to SHIP1, is broadly expressed and abundant in glucoregulatory tissues. SHIP2 is phosphorylated in response to insulin and IGF1 stimulation, which leads to its translocation to sites near PI3K. In humans, polymorphisms in the SHIP2 genes are associated with the MS and T2D. These findings are supported in rodents, as SHIP2 expression levels are elevated in skeletal muscle and adipose tissue from obese and type 2 diabetic mice (279). Consistent with these findings, transgenic overexpression of SHIP2 led to IGT and insulin resistance in mice fed a normal chow diet (325) while targeted disruption of SHIP2 improved insulin sensitivity and protected mice from high-fat diet-induced obesity. PTEN was originally identified as a candidate tumor suppressor and was later found to share homology with protein tyrosine phosphatases (397). Overexpression of PTEN and SKIP are also shown to inhibit insulin action in cultured cells, although homozygous deletion of PTEN results in embryonic lethality due to tumor formation. Tissue selective deletion of PTEN in liver, skeletal muscle, fat, and pancreas appears to offer protection against insulin resistance and reductions in β-cell mass in the face of high-fat feeding and streptozotocin treatment, respectively (373,614,615,691). Interestingly, glucose tolerance and insulin sensitivity are reported in human subjects who possess germline mutations in the PTEN gene. Several population-screening studies have failed to identify a relationship between PTEN polymorphisms and T2D susceptibility; however, three variants were identified in Japanese diabetic patients (307), but the differences between the ethnic groups studied to date have yet to be explained. Great care should be taken when considering the role of PTEN as a target for therapeutic intervention as mutations in this gene are associated with tumorgenesis and neurological defects and neurodegenerative diseases. Clearly, PTEN is a critical regulator of many signaling systems throughout the body. Lipid phosphatases acting as therapeutic targets to combat insulin resistance and complications associated with T2D have been reviewed in detail previously (386, 568).

Downstream of PI3K, defective activation of aPKCs has also been observed in muscle from type 2 diabetic rats, monkeys, and humans [as reviewed in reference (187)]. This defect in aPKC signaling is at least in part due to impaired upstream signaling at IRS-1 and PI3K. Furthermore, insulin-stimulated AS160 phosphorylation is reduced in patients with T2D, although the GAP activity of AS160 appears to be specific for Rabs 2A, 8A, and 14 (334).

Protein tyrosine phosphatase 1B (PTP1B)

Protein tyrosine phosphatase is a negative regulator of insulin signal transduction as it dephosphorylates phosphotyrosine residues of the IR and IRS-1. In general, PTPases are redox sensitive enzymes and all share a common catalytic motif (21). Insulin induced ROS-mediated oxidation of critical AA residues in the catalytic domain of the enzyme leads to inactivation, and thus enhanced signal transduction downstream of the IR (225, 417). Indeed, low-level ROS production during insulin stimulation is critical for certain aspects of insulin signal transduction (404, 416).

In insulin-resistant states including obesity-associated insulin resistance, PTP1B expression and activity are elevated in muscle and adipose tissue from humans and rodents (13,701). Furthermore, polymorphisms in the PTPN1 gene confer increased phosphatase express in muscle; this is associated with insulin resistance and T2D (62, 159). Overexpression of PTP1B in mouse muscle or myocytes led to impaired insulin signal transduction of reduced glucose uptake and glycogen deposition (173, 720). Conversely, high-fat fed mice with genetic deletion of PTP1B (176, 357) and diabetic or obese animals treated with PTP1B antisense oligonucleotide (242,729) showed improved insulin sensitivity. In addition, mice lacking PTP1B are also protected from TNFα-induced insulin resistance (462). Thiazolidinedione (TZD)-induced insulin sensitization as well as exercise and caloric restriction interventions that improve whole body insulin sensitivity are associated with reduced PTP1B in skeletal muscle (14, 702). PTP1B as a therapeutic target to ameliorate insulin resistance associated with T2D has received greater attention and is reviewed in reference (362).

Inflammation and insulin signaling

Nuclear factor (NF)-κB and activating protein (AP)-1 are two central proinflammatory pathways activated in glucoregulatory tissues during overnutrition and in type 2 diabetic patients (Fig. ). Studies in rodents with inactivating mutations in the upstream kinases associated with these signaling pathways, IKKβ and JNK, have shown remarkable efficacy in preventing diet-induced insulin resistance, restraining obesity, and ameliorating T2D (28, 269). Interestingly, for over a century now it has been observed that aspirin (acetylsalicylic acid) exerts glucose lowering effects and can ameliorate certain complications associated with T2D, and work by Yuan and colleagues (717) has identified NF-κβ as the pharmacologic target of this antidiabetic agent. Recently, a favorable safety profile and a remarkable efficacy in reducing glycemia, insulin resistance, and diabetic complications, such as CVD, have been observed in clinical trials where salsalate, a prodrug form of salicylate, was administered to type 2 diabetic patients (198, 224).

In addition to the effects of these stress kinases, namely, IKKβ and JNK, to activate transcriptional inflammation programs leading to increased expression of cytokines and chemokines (e.g., TNFα, IL-6, IL-1, and MCP-1), both are thought to directly alter tyrosine kinase activity of proximal insulin signaling (10,11,269). It is currently thought that these stress kinases are activated by the intracellular accumulation of proinflammatory lipid intermediates including diacylglycerol (DAG) and ceramide although activation via cell surface toll-like receptors (TLRs) has also been implicated.

Toll-like receptors and cellular inflammation

TLRs are transmembrane protein receptors that are expressed in a variety of cell types and are critical for innate immune responses. TLRs are now viewed as an important molecular link between lipid oversupply and activation of proinflammatory signaling (207). While eleven members of the TLR family have been identified in humans and 13 in mice (508), of interest, TLR2 and TLR4 are expressed in glucoregulatory tissues including adipocytes, hepatocytes, and myocytes (382, 399). Furthermore in skeletal muscle cells and adipocytes, in vitro and in vivo evidence show that lipid oversupply causes TLR2/TLR4 upregulation, and this is associated with activation of stress-linked kinases (including p38, JNK, and PKC), as well as NF-κB nuclear translocation and subsequent transcription of downstream targets (Fig. 4) (583). Moreover, Tlr4-deficient rodents are protected against the obesigenic effects of a high-fat diet and, in addition, exhibit reduced cellular NF-κB activity including diminished circulating levels of MCP-1 (144). However, recent work shows that when accumulation of intracellular lipid intermediates including ceramide is prevented pharmacologically or genetically, long chain fatty acid-induced inflammatory signaling is also prevented; however, critically, TLR2/4 signaling by their specific ligands including lipoteichoic acid and lipopolysaccharide is maintained. Whether TLR2/4 are important and/or essential in the induction of the tissue inflammatory response in obese humans remains unknown. Clearly, critical work must be undertaken to identify the central mechanism(s) linking cellular uptake of saturated fatty acids with the activation of inflammatory signaling.

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Figure 4

Schematic illustrating mechanisms promoting inflammation that is now recognized as an important underpinning contributing in the pathogenesis of insulin resistance via impairment of insulin signal transduction. Abbreviations: AP-1, adaptor protein 1; IKK, I kappa B kinase; IKKkinase; IκB-α, inhibitor of kappa B; IL, interleukin; IRAK, interleukin receptor-associated kinase; JAK, janus kinase; JNK, c-Jun N-terminal kinase. Originally identified kinase family that binds and phosphorylates c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. MAPK2, mitogen-activated protein kinase 2; MAPK3, mitogen-activated protein kinase 3; NF-κB, nuclear factor κ B (nuclear factor kappa-light-chain-enhancer of activated B cells); RIP, receptor-interacting serine/threonine-protein kinase; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TLR, toll-like receptor; TRADD, tumor necrosis factor receptor type 1-associated DEATH domain protein (adaptor protein); TRAF, TNF receptor associated factors.

Fatty acid-binding proteins as lipid sensors

In 1981, Abumrad et al. (7) showed that cellular uptake of long chain fatty acids is saturable and involves a plasma membrane transport system. In 1991, cloning of the cDNA encoding human skeletal muscle fatty acid-binding protein (FABP), its peptide sequences and chromosomal localization was achieved by Peeters et al. (496). Two years later Abumrad et al. (6) cloned a rat adipocyte membrane protein homologous with human CD36 so named FAT/CD36, and in 1994, Schaffer et al. (574) cloned and characterized a novel adipocyte LCFA transport protein, FATP (Slc27a1). All of these are highly expressed in muscle and regulate LCFA uptake.

Fatty acid-binding proteins are abundantly expressed cytosolic (c) or membrane bound (pm) and coordinate cellular lipid metabolism, binding with high affinity, long-chain fatty acids and eicosanoids (127). FABPs are involved in FA import, storage, and export as well as cholesterol and phospholipids metabolism (258). Additionally, it is thought that FABPs are an adaptive lipid-sensing system, as their levels are altered during elevated fatty acid exposure, chronic endurance exercise (350, 653), genetic obesity, and pathology-associated nutrient changes (406, 641, 652, 654). Interestingly, recent work suggests that in addition to regulating the transport of fatty acids into the cell, FABPs may serve as coregulators of transcription factors known to modulate lipid metabolism and inflammation via a nucleocytoplasmic shuttling mechanism (266, 322, 699). The most actively studied interaction is between FABPs and the family of peroxisome proliferator-activated receptors (PPARs) including α, δ, and γ. Thus, it was hypothesized that selective modulation of FABPs may serve as a potential therapeutic mechanism to treat lipid- and inflammatory-associated diseases. Specifically, adipocyte and macrophage FABPs play a powerful role in regulating tissue inflammation and whole body glucose metabolism. Small molecule inhibitors of aP2 (FABP4) in macrophages blunt FABP activity and reduce cellular inflammation in a time- and dose-dependent fashion. aP2 inhibition is also shown to reduce lesion area in the proximal aorta of atherosclerosis prone Apoe−/− mice fed a Western diet (215). Similar findings were observed in mice with a genetic deletion of aP2 (FABP4) and mal1 (FABP5) in adipocytes and macrophages (411). Collectively, these studies provide substantial evidence that aP2 is an important regulator of cellular fatty acid handling, inflammation, and whole body glucose tolerance and insulin sensitivity. This work implicates lipid chaperones, FABPs, as potential clinically relevant therapeutic targets in the treatment of T2D and CVD; however, studies in human subjects are still required. It is also important to note that these binding proteins are upregulated with physical exercise (350,653) and fasting (652), from which a coordinated increase in fatty acid oxidation, repression of inflammation, and improved insulin sensitivity are achieved.

Protein fatty acid transporter FAT/CD36 expression is also elevated in response exercise training and the 88 kDa protein translocates rapidly to the plasma membrane during muscle contraction. Increased expression and activity of this transport protein contributes in large part to the fivefold to 15-fold increase in fatty acid uptake by contracting skeletal muscle (73,91,544). The protein is shown to colocalize with caveolin-3 and most highly abundant in type 1 oxidative muscle fibers (666). Interestingly, similar to GLUT4, FAT/CD36 is skeletal muscle is maintained under basal conditions in an intracellular pool and translocates to the plasma membrane primarily in response to contraction or insulin stimulation (74, 407). Over the past decade, it has been disputed whether FAT/CD and FATP-1 may be involved in deciding the metabolic fate of LCFA, specifically partitioning FAs to oxidation. Bezaire and colleagues put forth the notion that fatty acid transporters FAT/CD and FATP1 are involved in the transfer of FAs into the mitochondria possibly by direct binding to the mitochondrial membrane (66, 96). This work is recently disputed by Jeppesen et al. (315). Regardless of whether these proteins bind directly to mitochondria, at least in the case of FATP, skeletal muscle-specific overexpression in mice promoted increased skeletal muscle fatty acid uptake and oxidation specifically, but did not predispose animals to diet-induced insulin resistance (274). In aggregate, despite over two decades of intense research since their identification, it would seem that our understanding of the involvement of fatty acid binding proteins in regulating substrate metabolism, tissue inflammation, and insulin action requires further investigation.

Fatty acid handling

High-fat feeding or elevation of circulating fatty acid levels achieved by TG and heparin infusion are well known to cause skeletal muscle insulin resistance; however, the precise signaling events that underlie fatty acid-induced insulin resistance remain incompletely defined. It is currently held that excessive fatty acid uptake into the myocyte and reduced fat oxidation lead to the accumulation of proinflammatory lipid metabolites, such as fatty acyl CoAs, DAG, and ceramide, which, as stated above, activate serine/threonine “stress” kinases (Fig. 4). These kinases include JNK, IKKβ, and PKCθ, all of which promote inflammatory signaling and antagonize insulin action. Reduced expression of the rate limiting enzyme for LCFA entry into the mitochondria, carnitine palmitoyltransferase-1 (CPT1), and impaired mitochondrial function (decreased mitochondrial number, lower levels of oxidative enzymes, and lower ATP synthetic rates) are found in insulin-resistant skeletal muscle and coincide with muscle lipid accumulation (58, 351, 503, 541, 694). Furthermore, genes of oxidative metabolism were shown to be coordinately reduced in muscle from human patients with insulin resistance and T2D (450, 490). It is important to note that in human subjects these are merely observational and coincident changes in multiple signaling pathways; causal relationships between impairments in oxidative metabolism and mitochondrial function with insulin resistance is not established (253), and indeed there is evidence that in the condition of primary congenital insulin resistance, mitochondrial dysfunction follows (597). Additional longitudinal studies are necessary to delineate the pathogenesis and molecular underpinnings of this often-heterogeneous mix of metabolic disorders that characterize MS.

Despite this controversy and lack of mechanistic insight into the human pathology, several studies have shown that TG accumulation in skeletal muscle correlates most highly with insulin resistance, even when compared to other factors including BMI, percent body fat, and waist-to-hip ratio (313, 371, 499). TG accumulation is regulated directly and indirectly by several important enzymes located in the cytoplasm and mitochondria. For example, CPT1 is a key metabolic regulator of fatty acid oxidation, located in the outer mitochondrial membrane and in close proximity with acetyl-CoA carboxylase (ACC), a cytosolic enzyme that catalyzes the carboxylation of cytosolic acetyl CoA to form malonyl CoA, a potent inhibitor of CPT1. Malonyl-CoA levels are controlled by the relative activities of ACC and malonyl-CoA decarboxylase, the principal enzyme involved in malonyl CoA degradation. When malonyl CoA levels rise, mitochondrial fatty acid import, and oxidation are suppressed, thus favoring fatty acid storage in the form of TG. ACC inhibition, CPT1 activation, and enhanced fatty acid oxidation are previously shown to associate with insulin sensitivity and protection against diet-induced insulin resistance (118, 161). Importantly, in skeletal muscle from obese individuals, the activity of CPT1 is reduced (351) and may account for at least some of the decrement in skeletal muscle fatty acid oxidation observed in obesity and insulin resistance. This notion is consistent with recent work showing that CPT1 overexpression in myotubes (579) and murine skeletal muscle (87), or enhanced β-oxidation in mice harboring a null ACC2 mutation (118) is protective against diet-induced insulin resistance. Given that endurance exercise in rodents and humans is associated with elevated CPT1 activity levels and greater fatty acid oxidative capacity, therapies targeted at improving fatty acid flux through the tricarboxylic pathway to ameliorate insulin resistance are warranted. It is also important to note that while elevated TG levels correlate well with insulin resistance in type 2 diabetic and sedentary individuals, TG levels are also elevated in insulin sensitive highly trained athletes (556). The notion of the lipid paradox is well supported and suggests that other factors independent of TG, such as accumulation of more bioactive lipid species, including DAG or ceramide, and peroxidation of lipid bilayers promote inflammation and are the true culprits of insulin resistance (165, 226, 556). Stored muscle triacylglycerol is thought to be a biologically inert pool of stored fat in certain instances activation of TG synthesis may be advantageous in reducing the inflammatory consequences of nutrient excess. Identification of the precise causal factors underlying proinflammatory signaling and insulin resistance associated with increased muscle lipid storage in sedentary individuals compared with those engaging in daily exercise, is of biological and clinical interest.

Accumulation of bioactive lipid intermediates and insulin resistance

Indeed, there are mechanistic links between the development of insulin resistance and the accumulation of DAG and ceramide in muscle (8, 271, 272, 310), although, as put forward by Goodpaster and colleagues previously for triacyclyglycerol, a paradox for DAG in muscle of endurance-trained athletes is now also suggested (19). Dissecting the athlete’s paradox further, in sedentary individuals, a major contributor to increased lipid deposition is an impaired ability to oxidize fat as a fuel source (108, 593, 594). Elevated intracellular fatty acids are shown to induce enzymes that promote tissue sphin-golipid synthesis. Despite being a relatively small component of the total lipid pool, sphingolipids, such as ceramide and glucosylceramide, are considered the most pathogenic (618) and are elevated almost twofold in insulin-resistant obese compared with lean, sedentary or exercise-trained subjects (19). Four serial reactions promote the synthesis of ceramide from fatty acids and serine. Two of these enzymes, serine palmitoyl-transferase (SPT)-1 and dihydroceramide desaturase (Des-1), have received attention regarding their therapeutic potential to reverse insulin resistance and ameliorate complications associated with T2D. SPT-1 catalyzes the first reaction that condenses serine with palmitoyl-coenzyme A (CoA) to produce 3-ketosphinganine. This first reaction is the rate-limiting step in the synthesis of ceramide. SPT-1 is highly selective for saturated fatty acyl-CoA and the rate of this reaction is influenced largely by the availability of fatty acid substrate. Experimental elevation of fatty acids in rodents increases ceramide accumulation in skeletal muscle and liver and is associated with insulin resistance. However, coinfusion of an SPT-1 inhibitor, such as myriocin or cycloserine, prevents both lipid-induced ceramide accumulation and impaired insulin action (272). Similarly, myriosin administered to Zucker diabetic fatty rats reduces tissue ceramide levels, improves glycemia and circulating TG, and ameliorates glucose and insulin intolerance (271, 272). Des-1 oxidizes inactive dihydroceramide into active ceramide. In line with findings for myriosin-treated rodents, tissues harvested from Des-1+/− mice accumulate less ceramide and these animals are refractory to insulin resistance (271). Overall, these findings in rodents warrant further investigation in humans so as to discern whether SPT-1 and Des-1 are viable therapeutic targets to reverse insulin resistance and restrain T2D progression. Additionally, exhaustive exercise diminishes total content and saturation of ceramide and sphingomyelin-FA as well as activity of sphingomyelinase in oxidative muscles from rats (162) and vastus lateralis from humans (265).

Collectively, these findings in rodents warrant further investigation in humans to discern whether SPT-1 and Des-1 are viable therapeutic targets to reverse insulin resistance and restrain T2D progression by diminution of cellular bioactive lipids, including ceramides. Furthermore, it will be important to unravel mechanistic underpinnings of the athlete’s paradox to determine the site of uncoupling related to lipid accumulation for proinflammatory signaling. It is likely that mitochondrial content, lipid droplet localization, the precise molecular species of the lipid and the relative abundance and activity of potent transcriptional regulators of key pathways in metabolism, insulin action, and inflammation converge to explain the discrepancies in human populations and experimental mouse models.

Protective chaperones - heat shock protein response

Heat shock proteins (HSPs) are shown in murine models to block inflammation and protect against obesity-induced insulin resistance (120). HSPs are adaptive proteins that protect against cellular stress including alterations in temperature, pH, misfolded proteins, and inflammation (465). In humans, exercise training is also shown to cause increased tissue HSP levels; this adaptation is thought to be associated with disease prevention (85, 705). Thus, it is hypothesized that loss of heat shock response may underlie susceptibility to chronic disease while activation of the heat shock response may have broad therapeutic benefit in the treatment of such diseases including CVD and T2D. This notion is supported by work from Chung et al. (120), showing that upregulation of the inducible HSP, HSP72, either by heat stress, pharmacological or genetic means leads to protection against diet- and obesity-induced inflammation, glucose intolerance and insulin resistance. HSP72-mediated protection was associated with suppressed inflammatory signaling as well as improved oxidative metabolism (100); however, the precise mechanisms underlying the cellular and tissue-specific therapeutic actions of HSP72 require further elucidation. Indeed, follow-up studies by Gupte et al. (244) in heat-treated rats confirmed findings by Chung et al., showing that induction of Hsp72 protected against high fat diet-induced glucose intolerance and insulin resistance. Furthermore, reduction in activity of citrate synthase and mitochondrial cytochrome oxidase induced by high-fat feeding was prevented by one bout of thermal stress (244). Similarly, Geiger and colleagues also noted that one bout of thermal stress improves skeletal muscle insulin action in aged Fischer 344 rats, and this was associated with reduction in proinflammatory signaling (245). In addition muscle,

Given that muscle HSP72 expression is diminished in obese and type 2 diabetic patients (85, 120), studies are currently underway to investigate whether a novel investigational compound, which causes induction of HSP72, leads to improved insulin sensitivity and reversal of complications associated with T2D.

In addition to pharmaceutical intervention, endurance exercise also elevates Hsp72 mRNA and protein levels in skeletal muscle of humans and rodents (190, 191, 601) and the degree of Hsp72 induction is thought mediated by a variety of factors including muscle glycogen content (191), tissue hypoxia (636), the severity of exercise thermal stress, and or the degree of protein oxidation (601). In addition, activation of HSP72 by thermal stress conditioning is also shown to improve antioxidant capacity and this was associated with reduced muscle injury in rats following downhill running (589). The precise stimuli and mechanisms required for the induction of HSP72 during exercise requires further investigation as well as the molecular underpinnings mediating the therapeutic benefit of HSP72 elevation.

Endoplasmic reticulum stress

Evidence implicating inflammation, specifically endoplasmic reticulum (ER) stress in the etiology of β-cell apoptosis as well as liver and adipose tissue dysfunction is now well supported (281). It is clear that the capacity of the ER to adapt to stress is paramount for the maintenance of cellular health. The ER is the organelle responsible for protein folding, maturation, quality control, and trafficking. This organelle becomes “stressed” when newly synthesized unfolded proteins accumulate excessively in the lumen and, as a consequence, the unfolded protein response (UPR) is initiated to resolve the cellular stress. Importantly, the branches of the canonical UPR intersect with two main inflammatory pathways including NF-κB and JNK-AP1. In addition to the accumulation of unfolded nascent proteins, ER stress can also be induced by imbalances in calcium, glucose and energy deprivation, hypoxia, pathogen, toxins and certain lipids (281). Thus, cells specifically involved in handling and secreting large quantities of proteins, lipid, and lipid mediators are highly susceptible to ER stress and the cellular consequences of the UPR.

In the pancreas, lipotoxicity directly affects ER stress-mediated β-cell death (93). ER stress initiates a cascade of signaling events culminating in the attenuation of de novo protein synthesis and transcriptional activation of genes encoding ER chaperones to further assist in protein refolding or removal by the ubiquitin-proteosome pathway. An impaired or defective UPR leads to apoptosis. Markers of ER stress include PKR-like ER kinase (PERK), activating transcription factor (ATF), and inositol requiring (IRE)1. During cellular stress PERK becomes phosphorylated, leading to subsequent phosphorylation of eukaryotic initiation factor (EIF)2α, causing induction of ATF4. Additionally, ATF can also activate apoptotic pathways including C/EBP homologous protein (CHOP), JNK, and caspases. A strong link between ER stress signaling and β-cell function is evidenced by ER stress gene expression increased in islets from humans with T2D as well as db/ db mice (294, 385). Within the lumen of the ER, protein chaperones, such as BiP or GPR78, GPR94, calnexinm, and calrecticulin assist in the execution of proper protein folding and the elimination of misfolded or unfolded proteins. Phenylbutyrate (PBA) or BiP overexpression in INS-1 cells causes inactivation of IRE1, reduced ER stress, and prevention of palmitate-induced cell death (93). This work suggests that selective targeting of the UPR response in β-cells could prevent cellular apoptosis, preserve β-cell mass, and prevent T2D; however, evidence for this in humans is lacking.

In liver and adipose tissue samples from genetically obese or high-fat fed mice, markers of ER stress (increased PERK, EIF2α, and c-Jun phosphorylation) were elevated when compared to lean and normal chow fed controls (235, 486). This inflammatory stress response leads to suppression of insulin receptor signaling through hyperactivation of JNK and subsequent serine phosphorylation of IRS-1. X-box-binding protein (XBP)-1 is a bZIP protein that is spliced during ER stress and becomes a key transcriptional regulator of an array of genes that are important for ER stress resolution including the induction of molecular protein chaperones. In cells, the degree of ER stress induced by the chemical compound and JNK activator tunicamycin was directly impacted by XBP-1 expression; that is, cells overexpressing XBP-1 were refractory to ER stress. In vivo studies in rodents support cell-based studies as mice deficient (heterozygous null) in XBP-1 develop glucose intolerance and insulin resistance that is associated with tissue inflammation and impaired insulin signaling (486).

In follow-up studies by the same research group, 4-phenyl butyric acid and taurine-conjugated ursodeoxycholic acid were shown to alleviate ER stress in cells and rodents. Chemical or pharmaceutical chaperones, such as 4-phenyl butyric acid (PBA), trimethylamine N-oxide dihydrate (TMAO), and dimethyl sulfoxide, are a group of low molecular weight compounds known to stabilize protein conformation, improve ER folding capacity, and facilitate the trafficking of mutant proteins. Similarly, endogenous bile acids and derivatives including ursodeoxycholic acid and its taurine-conjugated derivative (TUDCA) are also shown to modulate ER function. Specifically, treatment of obese and diabetic mice with PBA and TUDCA resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissue (487), suggesting that chemical chaperones enhance the adaptive capacity of the ER and exhibit potent antidiabetic effects in rodents.

In humans, weight loss following gastric bypass (GBP) was associated with reduced ER stress in adipose and liver and a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity (236). Markers of ER stress in adipose tissue significantly decreased with weight loss including expression of Grp78 and spliced sXBP-1, as were phosphorylated EIF2α and JNK1. Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated EIF2α before surgery, which was reduced in post-GBP sections. Similarly, 8 weeks of daily endurance exercise reduced proinflammatory signaling and as well as PERK and EIF2α phosphorylation in adipose and liver from high-fat-fed rats (141). Interestingly, recent work from the Spiegelman laboratory shows that the UPR is initiated in skeletal muscle following an acute bout of treadmill exercise and is involved in mediating muscle adaptations when exercise is performed repetitively (700).

Collectively, these findings demonstrate that chronic ER stress is a central feature of peripheral insulin resistance and T2D and that pharmacologic manipulation of this pathway coupled with weight loss may offer a novel therapeutic strategy for treating these common chronic diseases. Whether endurance exercise provides a therapeutic benefit in ameliorating chronic ER stress associated with obesity and T2D requires further study. The role that muscle-specific ER stress plays in tissue remodeling and metabolic function is an emerging area of investigation also requiring greater delineation and mechanistic insight.

Adipose tissue as an endocrine organ

It is known for over a decade now that adipose tissue dysfunction is a central underpinning link to obesity in the pathogenesis of the MS and T2D (Fig. 5). Over the past decade adipose tissue has been redefined as a dynamic metabolic, endocrine organ secreting various cytokines, chemokines and adipokines in a paracrine, autocrine, and endocrine fashion. Much of this work is reviewed in references (71, 229, 515, 521, 669, 732). Adipose tissue is no longer simply considered a passive energy storage depot, but instead is now recognized as the largest endocrine organ in the body secreting more than a hundred factors including fatty acids, cytokines, chemokines, prostaglandins, and steroids. These factors can exert local paracrine effects or are released into the circulation yielding systemic effects on brain, liver, and skeletal muscle. These adipose-secreted factors regulate such processes such as glucose metabolism, appetite, inflammatory signaling, immune function, angiogenesis, blood pressure, and reproductive function. Given that adipose tissue comprises a heterogeneous mix of cell types, including macrophages and other immune cells, endothelial cells, vascular smooth muscle cells, fibroblasts/preadipocytes, and mature adipocytes, the interplay among these cell types and specific roles of each of these cells in adipose tissue development, substrate metabolism, and production of secretory factors are extremely complex and still not well understood.

Dysfunction within adipocytes specifically is an important contributor to the pathogenesis of obesity and T2D. Recent evidence suggests that enlarged adipocytes, relative impairment in tissue blood flow, cellular hypoxia, local inflammation, and adipose tissue infiltration of proinflammatory immune cells are interrelated processes thought to modulate adipocytes function including adipokine production and secretion; these important factors are reviewed in more detail elsewhere (229). Enlargement of adipocytes, frequently seen in obesity and consumption of a diet rich in saturated fatty acids, is associated with increased expression of proinflammatory adipocytokines whereas small adipocytes or therapies used to promote adipogenesis are associated with insulin sensitization (420, 445). While adipocyte size correlates well with insulin action and a favorable adipokine secretion profile, whether adipocytes size is a primary and central factor in determining adipose health remains to be determined, so herein we have focused on describing the effects of adipose-secreted demonstrating a regulatory role in modulating insulin sensitivity in vivo in both humans and rodents.


The identification of leptin (726), a 16-kDa cytokine-like peptide, and its receptor (114, 389, 634) initiated the burgeoning field of study into the role of adipose tissue as an endocrine organ. Leptin gained increasing attention in the late 1990s and this work fashioned leptin into a central regulator of feeding and energy homeostasis (209). Mice with mutations in the leptin gene or its receptor are remarkably obese (114, 208, 389). Likewise, human leptin mutations recapitulate an obese phenotype. A primary effect of leptin is exerted in the brain where the receptor is highly expressed in the hypothalamus. Leptin is shown to repress orexigenic pathways including neuropeptide Y and agouti-related peptide and activate anorexigenic pathways, pro-opiomelanocortin, and cocaine and amphetamine-regulated transcript (CART) (177, 179). The leptin receptor belongs to the IL-6 receptor family of class I cytokine receptors and exerts its central and peripheral effects on metabolism via the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) and PI3K (512). Leptin administration by intracerebral catheter directly into the brain decreases food intake and increases energy expenditure, and prolonged exposure leads to a reduction in total body weight (12).

Despite the known anorexic actions of leptin, administration of recombinant leptin as an obesity therapeutic proved futile given central leptin resistance that occurs with increasing adiposity. This is consistent with the many observations that leptin levels are markedly elevated in obese humans and rodents and correlate well with adiposity. Several regulators of leptin signaling have been proposed including SH2 containing SHP2 and protein tyrosine phosphatase 1B (PTP1B) and SOCS proteins. Early work by the Flier laboratory showed that leptin administration causes a rapid induction of hypothalamic Socs3 mRNA in mice and mediates feedback inhibition of the leptin receptor (67,68). Hypothalamic deletion of Socs3 (451) or whole body Socs3 haploinsufficiency (292) confers enhanced central leptin sensitivity and protection against diet-induced obesity. Furthermore, work by Levin et al. (396) showed that leptin-induced STAT3-phosphorylation, a surrogate marker for leptin receptor activation, was markedly reduced in the hypothalamic arcuate, ventromedial, and dorsomedial nuclei of high-fat fed rats even prior to obesity, while impaired leptin transport across the blood brain barrier was only observed after animals became obese. Collectively, these findings suggest that leptin resistance occurs early in the pathogenesis of obesity and that impaired receptor function is mediated by reduced receptor activation and expression mediated by Socs3 feedback inhibition.

In addition to the effects of leptin on the brain in the regulation of feeding, leptin also exerts direct effects in the periphery to improve insulin action independent of weight loss. Similar to the leptin resistance that develops in the brain, high-fat feeding can reduce leptin mediated effects in skeletal muscle (605, 607) and liver (672). Leptin resistance in muscle during high-fat feeding is thought to occur as a result of reduced leptin receptor expression (452) and elevated Socs3 mRNA (606, 608). A similar increase in Socs3 mRNA is also observed in skeletal muscle from obese subjects (606). Furthermore, Socs3 overexpression in human myotubes can prevent leptin-induced activation of AMPK (606).

Interestingly, swimming exercise improves hypothalamic leptin sensitivity and reduce food intake. Findings show that this exercise-induced effect is mediated by IL-6 (548, 549). While the dual roles of IL-6 in insulin action remain to be clarified, the collaborative work of Pedersen and Febbraio, clearly show that skeletal muscle IL-6 mRNA is rapidly induced at the onset of exercise and is secreted in abundance into the circulation. Furthermore, homozygous IL-6 deletion promotes hepatosteatosis and systemic insulin resistance (423). In addition to the effects of IL-6 on peripheral tissue metabolism, it is likely that IL-6 secreted from muscle during contraction is requisite for exercise-mediated effects in the brain given that IL-6 neutralization prevents exercise-mediated improvements in hypothalamic leptin signaling (199). Indeed, Steinberg et al. (608) also showed that endurance exercise can protect against high-fat diet-induced leptin resistance. Additional, studies are required to dissect apart the leptin-induced effects on metabolism mediated by the brain versus peripheral tissues in response to endurance exercise.


Adiponectin represents the most abundant protein secreted by adipose tissue (212) and adipose transcript as well as circulating levels of this protein are reduced in humans and in rodent models of obesity and T2D, as reviewed in references (27, 293, 323, 497, 645). A diabetes-susceptibility locus to human chromosome 3q27, where the adiponectin gene is located, and a quantitative-trait locus strongly linked to the MS in individuals of European and Asian descent have previously been identified (129, 256, 664). In rodents, administration of recombinant adiponectin or genetic overexpression lead to improved insulin sensitivity and enhanced fatty acid oxidation in liver and skeletal muscle (63, 212); while in contrast, genetic deletion is associated with glucose intolerance and insulin resistance (372, 412).

Adiponectin circulates in plasma as a low-molecular weight trimer, a mid-molecular weight hexamer, and a high-molecular weight 12- to 18-mer, and all forms are shown to exert differing biological function (670). The high molecular weight of adiponectin is thought to provide the greatest biological activity of all of the forms; however, additional work to substantiate this notion is required. However, Waki et al. (670) showed that impaired multimerization of human adiponectin is associated with T2D. Two distinct receptors, AdipoR1, which is expressed ubiquitously, and AdipoR2, which is expressed most abundantly in the liver, mediate the biological actions of adiponectin (707). Adiponectin binds and stimulates interaction of the N-terminal cytoplasmic domain of its receptor with and intracellular adaptor protein to activate intracellular pathways (418) including p38 MAPK, AMPK, and PPARα.

Accordant with reductions in circulating adiponectin levels observed in mouse models of insulin resistance and obesity, expression of both receptors was also shown to be diminished (706, 708). Experimental disruption of AdipoR1 or R2 causes blunted adiponectin-induced AMPK and PPARα responses, respectively, both leading to increased hepatic glucose production and hepatic insulin resistance (708). Conversely, adenoviral restoration of AdipoR1 or R2 in liver of diabetic mice improves adiponectin action leading to a partial restoration of insulin sensitivity (708). Interestingly, polymorphisms in both adiponectin receptors are associated with insulin resistance and T2D (135, 324, 429). An important aspect of adiponectin action includes anti-inflammatory effects to inhibit NF-κB and toll-like receptor signaling and these effects on immune cells and endothelium coupled with improved metabolism in peripheral tissues is thought to provide protection against atherosclerosis. In fact, when stratified for levels of serum adiponectin, the risk of myocardial infarction was dramatically reduced in men in the highest adiponectin quintile (504).

Thus taken together, improvement in adiponectin secretion or receptor function may serve as a therapeutic strategy to ameliorate the complications associated with insulin resistance and T2D. Consistent with this notion, it is thought that elevations in adiponectin and adiponectin receptors cause in large part TZD-induced insulin sensitization in type 2 diabetic subjects. Furthermore, recent evidence from reference (346) showed that 7 days of aerobic training (AT) increased circulating HMW adiponectin by 21%, and this alteration was associated with improved basal fat oxidation, glucose tolerance, and insulin sensitivity in middle-age obese individuals. The exercise-induced mechanisms and time course underlying enhanced adiponectin production by adipose tissue and whether corresponding changes in receptor function also occur requires further characterization.


In 2005, DNA arrays performed in adipose tissue from mice with an adipose specific deletion or overexpression of GLUT4 to identify adipose secreted factors that may be associated with insulin resistance; retinol binding protein (RBP)4 was identified (710). RBP4 is a circulating transport protein specific for retinol, vitamin A. RBP4 is elevated in tissue and in the circulation of insulin-resistant humans and rodents (234, 710). Furthermore, mice injected with recombinant RBP4 became insulin resistant while mice with a heterozygous or homozygous deletion of RBP4 were more insulin sensitive and protected from diet-induced insulin resistance. TZD and fenretinide, a synthetic retinoid, both lower circulating RBP4 levels in rodents, and this is associated with improved insulin action in rodent models of obesity and insulin resistance (710). There still remains some controversy with RBP4 and its relationship with obesity and its in vivo effects on the pathogenesis of insulin resistance in humans.


Lipocalin 2 (Lcn2), also known as neutrophil gelatinase-associated lipocalin, 24p3, and siderocalin, is a member of a large family of secreted proteins, including RBP4 that are associated with insulin resistance (106, 673, 709, 725). Lcn2 is an iron transport protein and its expression is induced in 3T3L1 adipocytes by TNFα and dexamethasone (709). In addition to being expressed in adipocytes, Lcn2 is also expressed in neutrophils, liver, kidney, and macrophages (673). Importantly, Lcn2 expression is elevated in visceral fat from obese human subjects (106), as well as adipose and serum from multiple rodent models of obesity and insulin resistance (709, 725). In addition, the circulating Lcn2 concentration is positively correlated with human adiposity, hypertriglyceridemia, CRP, and hyperglycemia but negatively correlated with HDL (673). Retroviral delivery of short hairpin RNA into 3T3L1 adipocytes yielding reduced Lcn2 expression was associated with improved insulin action while exogenous Lcn2 promoted insulin resistance in cultured hepatocytes (709). In addition, thiazolidindione-induced insulin sensitization in rodent models of obesity also causes reduced adipose tissue Lcn2 expression. Therefore, taken together, it is thought that lipocalin 2 is an adipokine that may be involved in potentiating obesity-induced insulin resistance.


The serine protease inhibitor pigment epithelium-derived factor (PEDF) is predominantly released from adipocytes and recently was shown to play a causal role in metabolic dysfunction and insulin resistance. PEDF is elevated in obese, insulin-resistant mice, and reduced upon insulin sensitization. Lean mice injected with recombinant PEDF exhibit insulin resistance during hyperinsulinemic-euglycemic clamps, while neutralizing PEDF in obese mice enhances insulin sensitivity (136). PEDF is also shown to alter whole body fatty acid metabolism by increasing adipose tissue lipolysis and decreasing fatty acid oxidation in skeletal muscle, resulting in ectopic lipid deposition in muscle and liver. Together, these results support a causal role for PEDF in obesity-induced metabolic dysfunction and insulin resistance (136, 186).


Resistin, first described by Steppan et al. (610), is a cytokine expressed exclusively in adipocytes in mice but is expressed predominantly in macrophages in human subjects (489). Resistin was identified as a TZD-downregulated gene in mouse adipocytes (610) and TZD therapy is also shown to reduce macrophage expression and levels of circulating resistin in humans (489). Furthermore, circulating resistin levels are elevated with obesity (516); experimental resistin elevation in rodents using acute administration (516), adenoviral-mediated delivery (570), and transgenic overexpression (519) is shown to induce insulin resistance. Consistent with these observations, loss-of-function mutations, achieved by antibody neutralization (610), genetic deletion (44), and anti-sense oligonucleotide administration (459) leads to improved insulin sensitivity and glucose homeostasis.

The receptor for resistin remains unknown and the details regarding resistin action to induce insulin resistance in glucoregulatory tissues is not completely understood; however, downstream of its putative receptor, resistin appears to inhibit hepatic and skeletal muscle AMPK (44, 459, 570). AMPK is known as the master energy regulator and controls substrate production and utilization in liver and muscle, respectively. In addition, findings in adipocytes suggest that resistin is also capable of activating Socs3 that was previously shown to cause impaired insulin action (612). While a clear relationship between circulating resistin levels and obesity/T2D in humans remains ill defined, differences in assay type and the existence of multiple higher molecular weight oligomers may contribute to the discrepant observations. Resistin levels do, however, correlate well with other inflammatory factors, including CRP peptide and the presence of atherosclerosis (318,472,529,588,611). In humans, this observation is particularly relevant given that resistin is predominantly produced by macrophages, a cell type central in the pathogenesis of arterial lesion development. Lastly, there is genetic support that resistin may play a role in T2D susceptibility given that a single nucleotide polymorphism in the promoter region is linked with obesity and insulin resistance in several populations in the United States, Japan, and Europe (117, 121, 479, 598).

Visfatin, omentin, chemerin, adipsin, ASP

Visfatin is a 52 kDA protein that is highly expressed in visceral but not adipose tissue from obese type 2 diabetic rodents (214). In humans, visfatin is correlated with visceral adipose mass and is upregulated during adipogenic differentiation; thus, plasma levels track well in some studies with human obesity. Interestingly, visfatin binds to the insulin receptor with the same affinity as insulin and promotes adipogenesis, an observation consistent with increased visfatin secretion rates from adipocytes following treatment with the PPARγ agonist rosiglitazone (250). Many unanswered questions remain as to the mechanistic role that visfatin may play in the pathogenesis of obesity and insulin resistance.

Omentin is a 38 kDa protein primarily expressed in omental fat and is thought to be secreted primarily from stromal vascular cells, not adipocytes, within the tissue compartment (711). Little is known about the physiological role of this protein, however, some studies suggest it is regulated by glucose and insulin and is associated with obesity cardiovascular syndromes (630).

Chemerin, also known as tazarotene-induced gene 2 or retinoic acid receptor responder 2 is an 18-kDa novel adipokine expressed predominantly in mature 3T3L1 adipocytes and is elevated in adipose tissue collected from obese animals. Chemerin is secreted as an inactive proprotein and is converted to its biologically active form following C-terminal proteolytic cleavage. While two studies published in 2007 (230, 546) suggest that chemerin modulates adipogenesis and that receptors for the adipokine are present in immune cells, little is known regarding the functional role of this adipokine or its true relationship to disease pathology. Recent work by Ernst et al. (181) show that chemerin and its receptors chemokine-like receptor 1, C-C motif receptor-like 2, and G protein-coupled receptor 1 (341) are altered in white adipose, liver, and skeletal muscle of obese type 2 diabetic mice. Administration of chemerin exacerbates glucose intolerance in these animals, thus, suggesting a role for chemerin in glucose homeostasis (181). Two independent studies by Bozaoglu et al. (79,80) found that circulating chemerin levels associate with obesity and the MS in Caucasian and Mexican-American populations. Furthermore, experimental hyperinsu-linemia caused a rapid induction of chemerin expression in adipose tissue explants and led to increased chemerin cellular protein level and secretion of chemerin into the conditioned media. Insulin-induced adipose tissue chemerin production was markedly reduced by the addition of metformin, a clinically utilized antidiabetic drug, to the media (631). In addition, a recent report by Ress et al. (533) showed that weight loss achieved by bariatic surgery resulted in significantly reduced circulating chemerin. These findings are consistent with at least a permissive if not a regulatory role for chemerin in glucose metabolism.

In vitro findings from Sell et al. (582) suggest the latter as chemerin release from in vitro differentiated human adipocytes and adipose tissue explants were elevated in the obese versus lean subjects. Additionally, chemerin release is correlated with BMI, waist-to-hip ratio, and adipocyte volume. Higher chemerin release also associated with insulin resistance. Ex vivo chemerin treatment induced insulin resistance in human skeletal muscle cells at the level of IRS 1, Akt and glycogen synthase (GS) kinase 3 phosphorylation, and glucose uptake (582). Chemerin also activated p38 mitogen-activated protein kinase, NF-κB, and extracellular signal-regulated kinase (ERK)-1/2. Given these recent findings and the known chemoattractant properties of chemerin, it is thought that a reduction in circulating chemerin may diminish the infiltration of proinflammatory immune cells in adipose tissue leading to restrained adipose tissue growth, thus, exerting both direct and indirect effects on peripheral tissues to regulate insulin action.

Adipsin is also known as adipocyte trypsin, factor D, or complement factor D (547). The protein encoded by the CFD gene is a member of the trypsin family of peptidases and a protein component of the alternative complement pathway. Recent evidence shows that this serine protease is expressed at high levels in adipose tissue and is secreted by adipose tissue explants. Furthermore, tissue expression levels and circulating concentration levels in the blood are elevated in obese subjects. In addition, adipose tissue also releases a protein derived from the interactions of adipsin with complement C3 and factor B known as acylation-stimulated protein (ASP). ASP is produced in a two-step process in which the aforementioned three proteins of the alternative complement system in which the enzyme adipsin causes cleavage of the parent protein C3 to C3a, which is followed by desargination of the carboxyl terminus to generate C3adesArg or ASP (124). Adipocytes are one of the few cell types that contain all three complement factors necessary for the generation of ASP. ASP is thought to represent the most biologically active component of this system and circulating levels are thought to be modulated by insulin, cytokines, and the fatty acid components of chylomicrons as reflected by dietary fat consumption. ASP is shown to exert potent effects to stimulate TG synthesis and inhibit lipolysis in adipocytes. ASP administration to obese or diabetic rodents enhanced TG clearance by as much as twofold; similar but less robust findings were also observed for lean control mice (457, 562). In part, TG synthesis is promoted by ASP-stimulated increases in diglycerol acyltransferase activity and glucose uptake into adipocytes, and these effects may be mediated by activation of specific adipocyte protein kinases, for example PKC (39). Mice with a homozygous null mutation for C3, and therefore ASP, showed altered postprandial TG clearance (456

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