Nature 456, 997-1000 (18 December 2008) | doi:10.1038/nature07541; Received 15 April 2008; Accepted 14 October 2008; Published online 26 November 2008

Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology

Theresa Alenghat1,2, Katherine Meyers1,2, Shannon E. Mullican1,2, Kirstin Leitner1,2, Adetoun Adeniji-Adele3, Jacqueline Avila1,2, Maja Buc acutean3, Rexford S. Ahima1,2, Klaus H. Kaestner2,3 & Mitchell A. Lazar1,2

  1. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine,
  2. The Institute for Diabetes, Obesity, and Metabolism, and,
  3. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Correspondence to: Mitchell A. Lazar1,2 Correspondence and requests for materials should be addressed to M.A.L. (Email: lazar@mail.med.upenn.edu).

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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