title: Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein.
abstract: 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.
authors.affiliation: Department of Medicine and Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Zhou
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shibusawa
authors.forename: Karuna
authors.initials: K
authors.lastname: Naik
authors.forename: Delia
authors.initials: D
authors.lastname: Porras
authors.forename: Karla
authors.initials: K
authors.lastname: Temple
authors.forename: Hesheng
authors.initials: H
authors.lastname: Ou
authors.forename: Kelly
authors.initials: K
authors.lastname: Kaihara
authors.forename: Michael W
authors.initials: MW
authors.lastname: Roe
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brady
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
mesh_terms: 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*
chemical_list: 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