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

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Listed:
  • 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)

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.

Suggested Citation

  • 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, 2005. "The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism," Nature, Nature, vol. 437(7062), pages 1109-1114, October.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7062:d:10.1038_nature03967
    DOI: 10.1038/nature03967
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    Cited by:

    1. Qingwen Zhao & Xuan Cui & Qi Zhu & Feiyan Li & Ran Bao & Ting Shi & Haojie Liu & Wenjing Lv & Yingjiang Xu & Yue Gao & Qi-Qun Tang & Min Zhang & Dongning Pan, 2025. "Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis," Nature Communications, Nature, vol. 16(1), pages 1-15, December.

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