1. Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030, USA
2. Department of Biotechnology, Institute of Molecular and Cell Biology, Tartu University, Tartu, 51010, Estonia
3. *These authors contributed equally to this work

Correspondence to: Cheng Chi Lee¹ Correspondence and requests for materials should be addressed to C.C.L. (Email: cheng.c.lee@uth.tmc.edu).

Abstract

Environmental light is the 'zeitgeber' (time-giver) of circadian behaviour¹. Constant darkness is considered a 'free-running' circadian state. Mammals encounter constant darkness during hibernation². Ablation of the master clock synchronizer, the suprachiasmatic nucleus, abolishes torpor, a hibernation-like state, implicating the circadian clock in this phenomenon^{2, 3}. 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^-/-/mPer2^m/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.

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