Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology

Theresa Alenghat, Katherine Meyers, Shannon E. Mullican, Kirstin Leitner, Adetoun Adeniji-Adele, Jacqueline Avila, Maja Bućan, Rexford S. Ahima, Klaus H. Kaestner and Mitchell A. Lazar ()
Additional contact information
Theresa Alenghat: Diabetes, and Metabolism
Katherine Meyers: Diabetes, and Metabolism
Shannon E. Mullican: Diabetes, and Metabolism
Kirstin Leitner: Diabetes, and Metabolism
Adetoun Adeniji-Adele: University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Jacqueline Avila: Diabetes, and Metabolism
Maja Bućan: University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Rexford S. Ahima: Diabetes, and Metabolism
Klaus H. Kaestner: The Institute for Diabetes, Obesity, and Metabolism, and,
Mitchell A. Lazar: Diabetes, and Metabolism

Nature, 2008, vol. 456, issue 7224, 997-1000

Abstract: Lean and quick Nuclear receptor corepressor 1 (Ncor1) is an activator for the enzyme histone deacetylase 3 (Hdac3) that is required for embryogenesis, but its physiological functions are unknown. Now experiments in knock-out mice lacking Ncor1 show that disruption of the Ncor1–Hdac3 interaction causes aberrant regulation of clock genes and results in abnormal circadian behaviour — with a sleep–wake cycle closer to 23 hours than the normal 24. These mice are also leaner than normal and more insulin sensitive as a result of increased energy expenditure. Loss of a functional Ncor1–Hdac3 complex in vivo changes the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. Targeting of the Ncor1–Hdac3 enzyme could be a highly specific intervention in diseases of nutritional stress such as obesity and diabetes.

Date: 2008
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DOI: 10.1038/nature07541

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