The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism

Seung-Hoi Koo, Lawrence Flechner, Ling Qi, Xinmin Zhang, Robert A. Screaton, Shawn Jeffries, Susan Hedrick, Wu Xu, Fayçal Boussouar, Paul Brindle, Hiroshi Takemori and Marc Montminy ()
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Seung-Hoi Koo: Salk Institute for Biological Studies
Lawrence Flechner: Salk Institute for Biological Studies
Ling Qi: Salk Institute for Biological Studies
Xinmin Zhang: Salk Institute for Biological Studies
Robert A. Screaton: Salk Institute for Biological Studies
Shawn Jeffries: Salk Institute for Biological Studies
Susan Hedrick: Salk Institute for Biological Studies
Wu Xu: St Jude Children's Research Hospital
Fayçal Boussouar: St Jude Children's Research Hospital
Paul Brindle: St Jude Children's Research Hospital
Hiroshi Takemori: Osaka University
Marc Montminy: Salk Institute for Biological Studies

Nature, 2005, vol. 437, issue 7062, 1109-1114

Abstract: Abstract Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon, and at the cellular level by energy status. Glucagon enhances glucose output from the liver during fasting by stimulating the transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (CRE binding protein). When cellular ATP levels are low, however, the energy-sensing kinase AMPK inhibits hepatic gluconeogenesis through an unknown mechanism. Here we show that hormonal and energy-sensing pathways converge on the coactivator TORC2 (transducer of regulated CREB activity 2) to modulate glucose output. Sequestered in the cytoplasm under feeding conditions, TORC2 is dephosphorylated and transported to the nucleus where it enhances CREB-dependent transcription in response to fasting stimuli. Conversely, signals that activate AMPK attenuate the gluconeogenic programme by promoting TORC2 phosphorylation and blocking its nuclear accumulation. Individuals with type 2 diabetes often exhibit fasting hyperglycaemia due to elevated gluconeogenesis; compounds that enhance TORC2 phosphorylation may offer therapeutic benefits in this setting.

Date: 2005
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DOI: 10.1038/nature03967

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