Dual role of the coactivator TORC2 in modulating hepatic glucose output and insulin signaling

Gianluca Canettieri; Seung Hoi Koo; Rebecca Berdeaux; Jose Heredia; Susan Hedrick; Xinmin Zhang; Marc Montminy

doi:10.1016/j.cmet.2005.09.008

Dual role of the coactivator TORC2 in modulating hepatic glucose output and insulin signaling

Gianluca Canettieri, Seung Hoi Koo, Rebecca Berdeaux, Jose Heredia, Susan Hedrick, Xinmin Zhang, Marc Montminy

Research output: Contribution to journal › Article › peer-review

59 Citations (Scopus)

Abstract

Under fasting conditions, the cAMP-responsive CREB coactivator TORC2 promotes glucose homeostasis by stimulating the gluconeogenic program in liver. Following its nuclear translocation in response to elevations in circulating glucagon, TORC2 regulates hepatic gene expression via an association with CREB on relevant promoters. Here, we show that, in parallel with their effects on glucose output, CREB and TORC2 also enhance insulin signaling in liver by stimulating expression of the insulin receptor substrate 2 (IRS2) gene. The induction of hepatic IRS2 during fasting appears critical for glucose homeostasis; knockdown of hepatic IRS2 expression leads to glucose intolerance, whereas hepatic IRS2 overexpression attenuates the gluconeogenic program and reduces fasting glucose levels. By stimulating the expression of IRS2 in conjunction with gluconeogenic genes, the CREB:TORC2 pathway thus triggers a feedback response that limits glucose output from the liver during fasting.

Original language	English
Pages (from-to)	331-338
Number of pages	8
Journal	Cell Metabolism
Volume	2
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2005.09.008
Publication status	Published - 2005 Nov
Externally published	Yes

Bibliographical note

Funding Information:
We thank members of the Montminy laboratory for helpful discussions. This work was supported by National Institutes of Health grant GM RO1-37828, by the Hillblom Foundation, and by the Keickhefer Foundation. G.C. is a recipient of a Juvenile Diabetes Research Foundation fellowship award and S.-H.K. is supported by an American Diabetes Association training fellowship award.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2005.09.008

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title = "Dual role of the coactivator TORC2 in modulating hepatic glucose output and insulin signaling",

abstract = "Under fasting conditions, the cAMP-responsive CREB coactivator TORC2 promotes glucose homeostasis by stimulating the gluconeogenic program in liver. Following its nuclear translocation in response to elevations in circulating glucagon, TORC2 regulates hepatic gene expression via an association with CREB on relevant promoters. Here, we show that, in parallel with their effects on glucose output, CREB and TORC2 also enhance insulin signaling in liver by stimulating expression of the insulin receptor substrate 2 (IRS2) gene. The induction of hepatic IRS2 during fasting appears critical for glucose homeostasis; knockdown of hepatic IRS2 expression leads to glucose intolerance, whereas hepatic IRS2 overexpression attenuates the gluconeogenic program and reduces fasting glucose levels. By stimulating the expression of IRS2 in conjunction with gluconeogenic genes, the CREB:TORC2 pathway thus triggers a feedback response that limits glucose output from the liver during fasting.",

author = "Gianluca Canettieri and Koo, {Seung Hoi} and Rebecca Berdeaux and Jose Heredia and Susan Hedrick and Xinmin Zhang and Marc Montminy",

note = "Funding Information: We thank members of the Montminy laboratory for helpful discussions. This work was supported by National Institutes of Health grant GM RO1-37828, by the Hillblom Foundation, and by the Keickhefer Foundation. G.C. is a recipient of a Juvenile Diabetes Research Foundation fellowship award and S.-H.K. is supported by an American Diabetes Association training fellowship award.",

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doi = "10.1016/j.cmet.2005.09.008",

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AU - Canettieri, Gianluca

AU - Koo, Seung Hoi

AU - Berdeaux, Rebecca

AU - Heredia, Jose

AU - Hedrick, Susan

AU - Zhang, Xinmin

AU - Montminy, Marc

N1 - Funding Information: We thank members of the Montminy laboratory for helpful discussions. This work was supported by National Institutes of Health grant GM RO1-37828, by the Hillblom Foundation, and by the Keickhefer Foundation. G.C. is a recipient of a Juvenile Diabetes Research Foundation fellowship award and S.-H.K. is supported by an American Diabetes Association training fellowship award.

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N2 - Under fasting conditions, the cAMP-responsive CREB coactivator TORC2 promotes glucose homeostasis by stimulating the gluconeogenic program in liver. Following its nuclear translocation in response to elevations in circulating glucagon, TORC2 regulates hepatic gene expression via an association with CREB on relevant promoters. Here, we show that, in parallel with their effects on glucose output, CREB and TORC2 also enhance insulin signaling in liver by stimulating expression of the insulin receptor substrate 2 (IRS2) gene. The induction of hepatic IRS2 during fasting appears critical for glucose homeostasis; knockdown of hepatic IRS2 expression leads to glucose intolerance, whereas hepatic IRS2 overexpression attenuates the gluconeogenic program and reduces fasting glucose levels. By stimulating the expression of IRS2 in conjunction with gluconeogenic genes, the CREB:TORC2 pathway thus triggers a feedback response that limits glucose output from the liver during fasting.

AB - Under fasting conditions, the cAMP-responsive CREB coactivator TORC2 promotes glucose homeostasis by stimulating the gluconeogenic program in liver. Following its nuclear translocation in response to elevations in circulating glucagon, TORC2 regulates hepatic gene expression via an association with CREB on relevant promoters. Here, we show that, in parallel with their effects on glucose output, CREB and TORC2 also enhance insulin signaling in liver by stimulating expression of the insulin receptor substrate 2 (IRS2) gene. The induction of hepatic IRS2 during fasting appears critical for glucose homeostasis; knockdown of hepatic IRS2 expression leads to glucose intolerance, whereas hepatic IRS2 overexpression attenuates the gluconeogenic program and reduces fasting glucose levels. By stimulating the expression of IRS2 in conjunction with gluconeogenic genes, the CREB:TORC2 pathway thus triggers a feedback response that limits glucose output from the liver during fasting.

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Dual role of the coactivator TORC2 in modulating hepatic glucose output and insulin signaling

Abstract

Bibliographical note

ASJC Scopus subject areas

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