Journal Article

Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology

Bućan, Maja, Leitner, Kirstin, Avila, Jacqueline, Kaestner, Klaus H., Mullican, Shannon E., Ahima, Rexford S., Meyers, Katherine, Alenghat, Theresa, Lazar, Mitchell A., Adeniji-Adele, Adetoun

2008

Overview

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. This paper shows that specific genetic disruption of the Ncor–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 due to increased energy expenditure. Loss of a functional Ncor–HdaC3 complex in vivo changes the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications 1 , 2 , 3 . Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology 4 , 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 physiology 9 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Amino Acid Substitution / Anatomy & physiology / Animals / ARNTL Transcription Factors / Basic Helix-Loop-Helix Transcription Factors - genetics / Biological and medical sciences / Biological Clocks - genetics / Biological Clocks - physiology / Cells, Cultured / Chronobiology / Circadian rhythm / Circadian Rhythm - genetics / Circadian Rhythm - physiology / Circadian rhythms / Diet / Energy balance / Energy Metabolism - genetics / Energy Metabolism - physiology / Female / Fundamental and applied biological sciences. Psychology / Gene Expression Regulation / Genetic aspects / Health aspects / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Histones / Humanities and Social Sciences / letter / Liver - enzymology / Liver - metabolism / Male / Metabolism / Mice / Mice, Inbred C57BL / multidisciplinary / Mutation / Neurons / Nuclear Proteins - chemistry / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Nuclear Receptor Co-Repressor 1 / Obesity - enzymology / Obesity - genetics / Obesity - metabolism / Physiology / Proteins / Repressor Proteins - chemistry / Repressor Proteins - genetics / Repressor Proteins - metabolism / Rodents / Science / Science (multidisciplinary) / Stem cells / Vertebrates: anatomy and physiology, studies on body, several organs or systems