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Published Online March 19, 2009
Science DOI: 10.1126/science.1171641

Reports

Submitted on January 30, 2009
Accepted on March 9, 2009

Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis

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

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

* To whom correspondence should be addressed.
Shin-ichiro Imai , E-mail: imaishin{at}wustl.edu
Joseph Bass , E-mail: j-bass{at}northwestern.edu

{dagger}These authors contributed equally to this work.

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 NAD+ biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations which 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.


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