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.
Bibliographical noteFunding 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
- Molecular Biology
- Cell Biology