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Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis

Abstract

During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis1. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element–binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)—two key transcriptional regulators of this process2. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment3,4,5,6. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A–mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein–coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with Gsα. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.

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Figure 1: Hepatic Creb-Crtc2 activity is modulated by the circadian clock.
Figure 2: Cry inhibits Creb activity.
Figure 3: Cry blocks induction of the gluconeogenic genetic program by Creb and Crtc2.
Figure 4: Cry inhibits GPCR-dependent increases in adenyl cyclase activity.

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Acknowledgements

We thank L. Vera, A. Luzader, E. Rodrigo and X. Li for adenoviral injections, J. Altarejos and M. Lindstrom for mouse blood collection and glucose measurement and N. Goebel for preparing primary hepatocytes. We also thank M. Yamout and P. E. Wright for stimulating discussions and N. Gekakis, D. Welsh and S. Wang for reading the manuscript. This is manuscript 080809 of Genomics Institute of the Novartis Research Foundation, and the research was supported in part by grants from the US National Institutes of Health (R01 GM074868 and R01 MH051573 to S.A.K; R01 DK083834 and R01 DK049777 to M.M.). Y.L. is supported by the “One Hundred Talents” Program of the Chinese Academy of Sciences (No. 2010OHTP08) and Shanghai Pujiang Program (10PJ1411200) in China, and D.A.N. is supported by a fellowship (GM083585) from the US National Institutes of Health.

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E.E.Z. and S.A.K. conceived the project. E.E.Z., Y.L., M.M. and S.A.K. designed the research. E.E.Z., Y.L., R.D., P.Y.P., A.C.L., T.H., D.A.N., X.S., S.L. and Y.K. performed the experiments. E.E.Z. and Y.L. analyzed the data. E.E.Z., Y.L., D.A.B., M.M. and S.A.K. wrote the paper. This work is also supported in part by the Clayton Medical Research Foundation (CMRF), and M.M. is a Senior CMRF Investigator. M.M. is also supported by the Kieckhefer Foundation.

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Correspondence to Marc Montminy or Steve A Kay.

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S.A.K. is a cofounder of ReSet Therapeutics and is a member of its Scientific Advisory Board.

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Zhang, E., Liu, Y., Dentin, R. et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 16, 1152–1156 (2010). https://doi.org/10.1038/nm.2214

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