title: CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice.
abstract: Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of Clock(Δ19/Δ19) mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Menghong
authors.initials: M
authors.lastname: Yan
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Huang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Yuangao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Zhishui
authors.initials: Z
authors.lastname: He
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Changgui
authors.initials: C
authors.lastname: Dai
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences (J.L., B.Z., M.Y., R.H., Yu.W., Z.H., Y.Y., C.D., Yi.W., F.Z., Q.Z.), 200031 Shanghai, China; and School of Life Science and Technology (Q.Z.), Shanghai Tech University, Shanghai 200093, China.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Zhai
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D034741:RNA, Small Interfering; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D056564:Sirtuin 1