title: Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock.
abstract: Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms.
authors: 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.|Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Fabin
authors: F
authors: Dang
authors: 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.|Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Xiujie
authors: X
authors: Sun
authors: 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.|Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Xiang
authors: X
authors: Ma
authors: 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.|Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Rong
authors: R
authors: Wu
authors: 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.|Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Deyi
authors: D
authors: Zhang
authors: 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.
authors: Yaqiong
authors: Y
authors: Chen
authors: Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, NanGang District, Harbin 150001, China.
authors: Qian
authors: Q
authors: Xu
authors: 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.
authors: Yuting
authors: Y
authors: Wu
authors: 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.|Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Yi
authors: Y
authors: Liu
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D057906:Circadian Clocks / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger; D012694:Serine; D056926:CLOCK Proteins; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt