Constant darkness is a circadian metabolic signal in mammals

Nature. 2006 Jan 19;439(7074):340-3. doi: 10.1038/nature04368.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / blood
  • Animals
  • Blood Glucose / analysis
  • Cell Cycle Proteins
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • Colipases / genetics
  • Colipases / metabolism
  • Darkness*
  • Enzyme Precursors
  • Fatty Acids, Nonesterified / blood
  • Feeding Behavior
  • Female
  • Gene Expression Regulation*
  • Light
  • Lipase / genetics
  • Lipid Metabolism*
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / genetics
  • Period Circadian Proteins
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stress, Physiological / metabolism
  • Transcription Factors / genetics


  • Blood Glucose
  • Cell Cycle Proteins
  • Colipases
  • Enzyme Precursors
  • Fatty Acids, Nonesterified
  • Nuclear Proteins
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Protein Precursors
  • RNA, Messenger
  • Transcription Factors
  • Adenosine Monophosphate
  • procolipase
  • Lipase
  • pancreatic lipase related protein 2