CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ

Abstract

Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver1. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2–5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways1, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-γ, a key regulator of lipogenic genes6,7. CREB inhibits hepatic PPAR-γ expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-γ by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

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Figure 1: Mice deficient in hepatic CREB activity display a fatty liver phenotype.
Figure 2: PPAR-γ mediates effects of CREB on triglyceride metabolism in liver.
Figure 3: HES-1 is a direct CREB target in vivo.
Figure 4: HES-1 mediates CREB-dependent inhibition of the lipogenic pathway during fasting.

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Acknowledgements

We thank K. Suter and L. Vera for performing injections; S. Stifani, R. Kageyama, J. Auwerx, Y. Shi and T. Sudo for providing reagents; and G. Schuetz for CREB knockout mice. We also thank R. Evans for reviewing the manuscript, and I. Verma for support. This work was supported by the NIH (M.M.), the American Diabetes Association, the Hillblom Foundation and the Deutsche Forschungsgemeinschaft (S.H.). F.G. is also supported by Dipartimento di Scienze Biomediche, Università di Sassari, Italy.

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Correspondence to Marc Montminy.

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Herzig, S., Hedrick, S., Morantte, I. et al. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. Nature 426, 190–193 (2003). https://doi.org/10.1038/nature02110

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