Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein.
Hepatic gluconeogenesis is essential for maintenance of normal blood glucose concentrations and is regulated by opposing stimulatory (cyclic adenosine monophosphate, cAMP) and inhibitory (insulin) signaling pathways. The cAMP signaling pathway leads to phosphorylation of cAMP response element-binding (CREB) protein, resulting in recruitment of the coactivators CREB-binding protein (CBP) and p300 and subsequent activation of gluconeogenesis. Insulin signaling leads to phosphorylation of CBP at serine 436, a residue near its CREB-interacting domain, but it is unknown whether this event modulates cAMP signaling. Here, we show in vitro and in 'knock-in' mice that a mutant CBP (S436A) is aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose production. We propose that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CBP recruitment.
Zhou
Xiao Yan
XY
Department of Medicine and Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637, USA.
Shibusawa
Nobuyuki
N
Naik
Karuna
K
Porras
Delia
D
Temple
Karla
K
Ou
Hesheng
H
Kaihara
Kelly
K
Roe
Michael W
MW
Brady
Matthew J
MJ
Wondisford
Fredric E
FE
D000818:Animals; D050882:CREB-Binding Protein; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005942:Gluconates; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015290:Second Messenger Systems / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D005942:Gluconates; D007328:Insulin; D009687:Nuclear Proteins; D015534:Trans-Activators; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D005947:Glucose; C030691:gluconic acid