The Pentose Phosphate Pathway Regulates the Circadian Clock

Cell Metab. 2016 Sep 13;24(3):462-473. doi: 10.1016/j.cmet.2016.07.024. Epub 2016 Aug 18.


The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Behavior, Animal
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Cell Line
  • Circadian Clocks* / genetics
  • Drosophila melanogaster / physiology
  • Gene Expression Regulation
  • Humans
  • Mammals / physiology
  • NADP / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Organ Specificity / genetics
  • Oxidation-Reduction
  • Pentose Phosphate Pathway* / genetics
  • Signal Transduction / genetics
  • Transcription, Genetic


  • NF-E2-Related Factor 2
  • NADP
  • CLOCK Proteins