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.

Ubiquitous and Temperature-Dependent Neural Plasticity in Hibernators

“…These changes may underlie cognitive impairments in patients recovering from severe hypothermia, like those demonstrated by Walpoth et al (1997) where body temperature dropped as low as 17°C for several hours. To investigate this process in a homeotherm, it would be interesting to determine whether similar microstructural changes are occurring in a mouse model of torpor (Zhang et al, 2006). More research is needed to further understand the mechanisms driving this highly malleable system, the role that this form of neural plasticity plays in the unique adaptation of hibernators to the cold, and the resulting effects of these repeated neural changes on learning and memory.…”

Constant Darkness Is a Mammalian Biological Signal

“…creatic lipases (Squire et al 2003). Expression analysis of the gene encoding PLRP2 demonstrated that it was coordinately expressed with procolipase (Zhang et al 2006). These observations indicated that DD-activated gene regulation is part of a complex biological program and is not unique to procolipase.…”

“…(Zhang et al 2006). This microarray comparison identified a gene encoding procolipase that was highly expressed in the liver from the animal kept in DD.…”

“…These observations indicated that DD-activated gene regulation is part of a complex biological program and is not unique to procolipase. Exposing mice kept in DD to white light resulted in the shut down of the procolipase expression in the various organs (Zhang et al 2006). Together, these findings implicated a circulatory factor in the activation of procolipase expression during DD.…”

Integration of energy metabolism and the mammalian clock

“…Recently, 5'-AMP was recently found to serve as a circulating chemical cue that signals constant darkness and induces torpor, a hibernation-like state characterized by depressed body temperature and metabolic rate. 78,79 On the other hand, feeding mice with a high-fat diet leads to changes in free-running period, feeding behavior and clock gene expression. 80 These findings underscore the importance of nutritional cues as upstream signals that coordinate circadian clock and metabolic oscillations.…”