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Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures
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Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis.

Kathryn Moynihan Ramsey1, Jun Yoshino, Cynthia S Brace

  • 1Department of Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, IL 60208-3500, USA.

Science (New York, N.Y.)
|March 21, 2009
PubMed
Summary

Mice show daily rhythms in nicotinamide adenine dinucleotide (NAD+) biosynthesis enzyme NAMPT and NAD+ levels. This discovery reveals a feedback loop connecting NAMPT/NAD+ and SIRT1/CLOCK:BMAL1, impacting circadian clock regulation.

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Area of Science:

  • Chronobiology
  • Metabolism
  • Molecular Biology

Background:

  • The circadian clock synchronizes physiological processes with the daily light-dark cycle via a transcription-translation feedback loop.
  • Nicotinamide adenine dinucleotide (NAD+) is a crucial metabolite involved in energy metabolism and cellular processes.
  • The enzyme NAMPT is rate-limiting for NAD+ biosynthesis in mammals.

Purpose of the Study:

  • To investigate the regulation of NAMPT and NAD+ levels by the circadian clock machinery.
  • To elucidate the feedback mechanisms involving NAMPT/NAD+ and core clock components.

Main Methods:

  • Utilized mouse models to study circadian oscillations.
  • Employed genetic and pharmacological inhibition of NAMPT.
  • Analyzed the expression of clock genes (e.g., Per2) and protein complexes (e.g., CLOCK:BMAL1, SIRT1).

Main Results:

  • Demonstrated that NAMPT and NAD+ levels exhibit circadian oscillations in mice, regulated by core clock components.
  • Showed that NAMPT inhibition enhances Per2 oscillation by releasing CLOCK:BMAL1 from SIRT1-mediated suppression.
  • Identified that the transcription factor CLOCK up-regulates Nampt expression, establishing a feedback loop.

Conclusions:

  • The NAMPT/NAD+ pathway is integrated into the mammalian circadian clock.
  • A novel feedback loop exists between NAMPT/NAD+ and the SIRT1/CLOCK:BMAL1 complex, influencing circadian rhythmicity.
  • This interaction provides a molecular link between metabolism and circadian timing.