title: Glucagon-CREB/CRTC2 signaling cascade regulates hepatic BMAL1 protein.
abstract: Energy metabolism follows a diurnal pattern responding to the cycles of light and food exposures. Although food availability is a potent synchronizer of peripheral circadian clock in mammals, the underlying mechanism remains elusive. Here, we found that the temporal signals of fasting and refeeding hormones regulate the transcription of Bmal1, a key transcription activator of molecular clock, in the liver. During fasting, glucagon, a major fasting hormone, activates CREB/CRTC2 transcriptional complex that is recruited to Bmal1 promoter to induce its expression. Furthermore, we showed that CRTC2 is required for basal transcriptional regulation of Bmal1 by experiments using either adenovirus-mediated CRTC2 RNAi knockdown or primary Crtc2 null hepatocytes. On the other hand, insulin suppresses fasting-induced Bmal1 expression by inhibiting CRTC2 activity after refeeding. Taken together, our results indicate CRTC2 as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, the University of the Chinese Academy of Sciences, Beijing 100049, and.
authors.forename: Xiujie
authors.initials: X
authors.lastname: Sun
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, the University of the Chinese Academy of Sciences, Beijing 100049, and.
authors.forename: Fabin
authors.initials: F
authors.lastname: Dang
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, the University of the Chinese Academy of Sciences, Beijing 100049, and.
authors.forename: Deyi
authors.initials: D
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, the University of the Chinese Academy of Sciences, Beijing 100049, and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031.
authors.forename: Cui
authors.initials: C
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Wu
authors.affiliation: the Ministry of Education Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, liuyi@sibs.ac.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002940:Circadian Rhythm; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism; D005943:Gluconeogenesis; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009991:Oscillometry; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C493245:CRTC2 protein, human; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D007328:Insulin; D014157:Transcription Factors; D005934:Glucagon
keywords: CRTC2; Circadian Clock; Clock Gene; Glucagon; Glucocorticoid; Insulin; cAMP-response Element-binding Protein (CREB)