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Science 324 (5927): 651-654

Copyright © 2009 by the American Association for the Advancement of Science

Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis

Kathryn Moynihan Ramsey,1,2,3,* Jun Yoshino,6,* Cynthia S. Brace,6,* Dana Abrassart,1,2 Yumiko Kobayashi,1,2,3 Biliana Marcheva,1,2 Hee-Kyung Hong,2 Jason L. Chong,2 Ethan D. Buhr,2 Choogon Lee,4 Joseph S. Takahashi,2,5 Shin-ichiro Imai,6,{dagger} Joseph Bass1,2,3,{dagger}

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.

1 Department of Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, IL 60208–3500, USA.
2 Department of Neurobiology and Physiology, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, IL 60208–3500, USA.
3 NorthShore University Health System Research Institute and Department of Medicine, Evanston, IL 60201, USA.
4 Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
5 Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208, USA.
6 Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: imaishin{at}wustl.edu (S.I.); j-bass{at}northwestern.edu (J.B.)

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