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, Marc Montminy

Research output: Contribution to journalArticle

656 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1109-1114
Number of pages6
JournalNature
Volume437
Issue number7062
DOIs
Publication statusPublished - 2005 Oct 20
Externally publishedYes

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Transducers
Fasting
Carrier Proteins
Glucose
Gluconeogenesis
Glucagon
Phosphorylation
AMP-Activated Protein Kinases
Liver
Hyperglycemia
Cyclic AMP
Type 2 Diabetes Mellitus
Cytoplasm
Homeostasis
Adenosine Triphosphate
Hormones
Insulin
Genes
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Koo, S-H., Flechner, L., Qi, L., Zhang, X., Screaton, R. A., Jeffries, S., ... Montminy, M. (2005). The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature, 437(7062), 1109-1114. https://doi.org/10.1038/nature03967

The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. / Koo, Seung-Hoi; Flechner, Lawrence; Qi, Ling; Zhang, Xinmin; Screaton, Robert A.; Jeffries, Shawn; Hedrick, Susan; Xu, Wu; Boussouar, Fayçal; Brindle, Paul; Takemori, Hiroshi; Montminy, Marc.

In: Nature, Vol. 437, No. 7062, 20.10.2005, p. 1109-1114.

Research output: Contribution to journalArticle

Koo, S-H, Flechner, L, Qi, L, Zhang, X, Screaton, RA, Jeffries, S, Hedrick, S, Xu, W, Boussouar, F, Brindle, P, Takemori, H & Montminy, M 2005, 'The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism', Nature, vol. 437, no. 7062, pp. 1109-1114. https://doi.org/10.1038/nature03967
Koo S-H, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005 Oct 20;437(7062):1109-1114. https://doi.org/10.1038/nature03967
Koo, Seung-Hoi ; Flechner, Lawrence ; Qi, Ling ; Zhang, Xinmin ; Screaton, Robert A. ; Jeffries, Shawn ; Hedrick, Susan ; Xu, Wu ; Boussouar, Fayçal ; Brindle, Paul ; Takemori, Hiroshi ; Montminy, Marc. / The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. In: Nature. 2005 ; Vol. 437, No. 7062. pp. 1109-1114.
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