Dual role of the coactivator TORC2 in modulating hepatic glucose output and insulin signaling.
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.
Canettieri
Gianluca
G
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Koo
Seung-Hoi
SH
Berdeaux
Rebecca
R
Heredia
Jose
J
Hedrick
Susan
S
Zhang
Xinmin
X
Montminy
Marc
M
D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005215:Fasting; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection
C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010750:Phosphoproteins; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose