CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1

Authors

  • Ben Zhou,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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    • These authors contributed equally to this work.

  • Yi Zhang,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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    • These authors contributed equally to this work.

  • Fang Zhang,

    Corresponding author
    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
    • Address reprint requests to: Qiwei Zhai, Ph.D., Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. E-mail: qwzhai@sibs.ac.cn; fax: +86 21 5492 0291; or Fang Zhang, Ph.D., Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. E-mail: fzhang@sibs.ac.cn.

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    • These authors contributed equally to this work.

  • Yulei Xia,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Jun Liu,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Rui Huang,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Yuangao Wang,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Yanan Hu,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Jingxia Wu,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Changgui Dai,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Hui Wang,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Yanyang Tu,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Xiaozhong Peng,

    1. The State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yiqian Wang,

    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
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  • Qiwei Zhai

    Corresponding author
    1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China
    • Address reprint requests to: Qiwei Zhai, Ph.D., Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. E-mail: qwzhai@sibs.ac.cn; fax: +86 21 5492 0291; or Fang Zhang, Ph.D., Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. E-mail: fzhang@sibs.ac.cn.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by grants from the National Natural Science Foundation of China (31030022, 31200591, 31200595, and 81321062), the National Basic Research Program of China (2014CB542300 and 2009CB918403), the Program of Shanghai Subject Chief Scientist (11XD1405800), the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-EW-R-09), the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences (2012KIP309), and the SA-SIBS Scholarship Program.

Abstract

The protein deacetylase, sirtuin 1 (SIRT1), involved in regulating hepatic insulin sensitivity, shows circadian oscillation and regulates the circadian clock. Recent studies show that circadian misalignment leads to insulin resistance (IR); however, the underlying mechanisms are largely unknown. Here, we show that CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), two core circadian transcription factors, are correlated with hepatic insulin sensitivity. Knockdown of CLOCK or BMAL1 induces hepatic IR, whereas their ectopic expression attenuates hepatic IR. Moreover, circadian change of insulin sensitivity is impaired in Clock mutant, liver-specific Bmal1 knockout (KO) or Sirt1 KO mice, and CLOCK and BMAL1 are required for hepatic circadian expression of SIRT1. Further studies show that CLOCK/BMAL1 binds to the SIRT1 promoter to enhance its expression and regulates hepatic insulin sensitivity by SIRT1. In addition, constant darkness-induced circadian misalignment in mice decreases hepatic BMAL1 and SIRT1 levels and induces IR, which can be dramatically reversed by resveratrol. Conclusion: These findings offer new insights for coordination of the circadian clock and metabolism in hepatocytes by circadian regulation of hepatic insulin sensitivity via CLOCK/BMAL1-dependent SIRT1 expression and provide a potential application of resveratrol for combating circadian misalignment-induced metabolic disorders. (Hepatology 2014;59:2196–2206)

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