Nature Medicine10, 633 - 637 (2004)
Published online: 16 May 2004; | doi:10.1038/nm1050
Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein
Xiao Yan Zhou1, 2, Nobuyuki Shibusawa1, 2, Karuna Naik1, Delia Porras1, Karla Temple1, Hesheng Ou1, Kelly Kaihara1, Michael W Roe1, Matthew J Brady1
& Fredric E Wondisford1
1
Department of Medicine and Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637, USA.
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 pathways1. 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 gluconeogenesis2,
3,
4,
5. 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 signaling6. 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.
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