Constant darkness is a circadian metabolic signal in mammals

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 phenomenon2,3. 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-/-/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.