Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology

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Abstract

Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications1,2,3. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology4,5,6,7. The nuclear receptor corepressor 1 (Ncor1) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (Hdac3)8. Lack of Ncor1 is incompatible with life, and hence it is unknown whether Ncor1, and particularly its regulation of Hdac3, is critical for adult mammalian physiology9. Here we show that specific, genetic disruption of the Ncor1–Hdac3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behaviour. These mice are also leaner and more insulin-sensitive owing to increased energy expenditure. Unexpectedly, loss of a functional Ncor1–Hdac3 complex in vivo does not lead to sustained increases in known catabolic genes, but instead significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of Hdac3 by Ncor1 is a nodal point in the epigenetic regulation of circadian and metabolic physiology.

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Figure 1: Ncor1–Hdac3 regulates peripheral clock and circadian physiology.
Figure 2: DADm mice exhibit increased energy expenditure.
Figure 3: DADm mice are resistant to diet-induced obesity.
Figure 4: Activation of Hdac3 by Ncor1 regulates circadian metabolic gene expression in the liver.

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Acknowledgements

We thank W. Pear for providing EIIa-Cre C57BL/6 mice, G. Barnes and J. Rusche for providing MS-275, P. White and J. Tobias for bioinformatics assistance, and L. Yin, S.-H. You, M. Qatanani and other members of the Lazar laboratory for helpful discussions. We also thank J. Richa and The Transgenic Mouse Core, H. Collins and the Radioimmunoassay/Biomarkers Core, R. Dhir and the Metabolic Phenotyping Core of the Penn Diabetes and Endocrinology Research Center (DK19525), H. Fu and the Mouse Embryonic Stem Cell Core (DK49210) and the Morphology Core of the Center for Molecular Studies in Digestive and Liver Disease (DK50306 and DK49210) for consultation and services. This work was supported by National Institutes of Health grant DK43806 (to M.A.L.), and T.A. was supported by a National Research Training Grant in Developmental Biology.

Author Contributions T.A., M.B., K.H.K., R.S.A. and M.A.L. designed the research, T.A., K.M., K.L., A.A.-A., S.E.M. and J.A. acquired the data, T.A., A.A.-A., S.E.M., M.B., R.S.A. and M.A.L. analysed and interpreted the data, and T.A. and M.A.L. drafted the manuscript.

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Correspondence to Mitchell A. Lazar.

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Alenghat, T., Meyers, K., Mullican, S. et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456, 997–1000 (2008) doi:10.1038/nature07541

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