Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis

Science. 2009 May 1;324(5927):651-4. doi: 10.1126/science.1171641. Epub 2009 Mar 19.

Abstract

The circadian clock is encoded by a transcription-translation feedback loop that synchronizes behavior and metabolism with the light-dark cycle. Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1.

Publication types

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

MeSH terms

  • ARNTL Transcription Factors
  • Acrylamides / pharmacology
  • Adipose Tissue, White / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biological Clocks*
  • CLOCK Proteins
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Cell Line, Tumor
  • Circadian Rhythm*
  • Cytokines / antagonists & inhibitors
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Feedback, Physiological*
  • Gene Expression Regulation
  • Hepatocytes / metabolism
  • Humans
  • Liver / metabolism
  • Mice
  • NAD / biosynthesis*
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Nuclear Proteins / genetics
  • Period Circadian Proteins
  • Piperidines / pharmacology
  • Protein Binding
  • Sirtuin 1
  • Sirtuins / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription, Genetic

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Acrylamides
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cytokines
  • Enzyme Inhibitors
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Nuclear Proteins
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Piperidines
  • Trans-Activators
  • Transcription Factors
  • NAD
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, mouse
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Sirtuins