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 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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Acknowledgements
We thank J. Lopez, M. Connors, Y. Wang, C. Reardon-Aluis and G. Getz for technical assistance. The human FOXO1 cDNA was a gift from G. Grosveld (St. Jude Children's Research Center) and the mouse Crebbp cDNA from R. Goodman (Oregon Health Science University). This work was supported by a grant from the US National Institutes of Health (R01 DK-63349 to F.E.W.) and The University of Chicago Diabetes Research and Training Center (P60 DK-20595).
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Zhou, X., Shibusawa, N., Naik, K. et al. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nat Med 10, 633–637 (2004). https://doi.org/10.1038/nm1050
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DOI: https://doi.org/10.1038/nm1050
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