Calorie restriction regulates circadian clock gene expression through BMAL1 dependent and independent mechanisms

Sci Rep. 2016 May 12;6:25970. doi: 10.1038/srep25970.


Feeding behavior, metabolism and circadian clocks are interlinked. Calorie restriction (CR) is a feeding paradigm known to extend longevity. We found that CR significantly affected the rhythms in the expression of circadian clock genes in mice on the mRNA and protein levels, suggesting that CR reprograms the clocks both transcriptionally and post-transcriptionally. The effect of CR on gene expression was distinct from the effects of time-restricted feeding or fasting. Furthermore, CR affected the circadian output through up- or down-regulation of the expression of several clock-controlled transcriptional factors and the longevity candidate genes. CR-dependent effects on some clock gene expression were impaired in the liver of mice deficient for BMAL1, suggesting importance of this transcriptional factor for the transcriptional reprogramming of the clock, however, BMAL1- independent mechanisms also exist. We propose that CR recruits biological clocks as a natural mechanism of metabolic optimization under conditions of limited energy resources.

Publication types

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

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Caloric Restriction / adverse effects*
  • Circadian Clocks / drug effects*
  • Circadian Rhythm Signaling Peptides and Proteins / genetics*
  • Circadian Rhythm Signaling Peptides and Proteins / metabolism*
  • Cryptochromes / genetics
  • Cryptochromes / metabolism
  • Feeding Behavior
  • Gene Expression Regulation / drug effects
  • Liver / metabolism*
  • Mice
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Circadian Rhythm Signaling Peptides and Proteins
  • Cryptochromes
  • Period Circadian Proteins
  • CLOCK Proteins
  • Clock protein, mouse