title: Constant darkness is a circadian metabolic signal in mammals.
abstract: Environmental light is the 'zeitgeber' (time-giver) of circadian behaviour. Constant darkness is considered a 'free-running' circadian state. Mammals encounter constant darkness during hibernation. Ablation of the master clock synchronizer, the suprachiasmatic nucleus, abolishes torpor, a hibernation-like state, implicating the circadian clock in this phenomenon. Here we report a mechanism by which constant darkness regulates the gene expression of fat catabolic enzymes in mice. Genes for murine procolipase (mClps) and pancreatic lipase-related protein 2 (mPlrp2) are activated in a circadian manner in peripheral organs during 12 h dark:12 h dark (DD) but not light-dark (LD) cycles. This mechanism is deregulated in circadian-deficient mPer1-/-/mPer2m/m mice. We identified circadian-regulated 5'-AMP, which is elevated in the blood of DD mice, as a key mediator of this response. Synthetic 5'-AMP induced torpor and mClps expression in LD animals. Torpor induced by metabolic stress was associated with elevated 5'-AMP levels in DD mice. Levels of glucose and non-esterified fatty acid in the blood are reversed in DD and LD mice. Induction of mClps expression by 5'-AMP in LD mice was reciprocally linked to blood glucose levels. Our findings uncover a circadian metabolic rhythm in mammals.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030, USA.
authors.forename: Jianfa
authors.initials: J
authors.lastname: Zhang
authors.forename: Krista
authors.initials: K
authors.lastname: Kaasik
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Cheng Chi
authors.initials: CC
authors.lastname: Lee
mesh_terms: D000249:Adenosine Monophosphate / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D003089:Colipases / Q000235:genetics / Q000378:metabolism; D003624:Darkness; D004792:Enzyme Precursors; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005247:Feeding Behavior; D005260:Female; D005786:Gene Expression Regulation; D008027:Light; D008049:Lipase / Q000235:genetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D001786:Blood Glucose; D018797:Cell Cycle Proteins; D003089:Colipases; D004792:Enzyme Precursors; D005230:Fatty Acids, Nonesterified; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D014157:Transcription Factors; D000249:Adenosine Monophosphate; C037107:procolipase; D008049:Lipase; C075988:pancreatic lipase related protein 2