Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis.
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.
Ramsey
Kathryn Moynihan
KM
Department of Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, IL 60208-3500, USA.
Yoshino
Jun
J
Brace
Cynthia S
CS
Abrassart
Dana
D
Kobayashi
Yumiko
Y
Marcheva
Biliana
B
Hong
Hee-Kyung
HK
Chong
Jason L
JL
Buhr
Ethan D
ED
Lee
Choogon
C
Takahashi
Joseph S
JS
Imai
Shin-Ichiro
S
Bass
Joseph
J
D056930:ARNTL Transcription Factors; D000178:Acrylamides / Q000494:pharmacology; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D009243:NAD / Q000096:biosynthesis*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
D056930:ARNTL Transcription Factors; D000178:Acrylamides; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D010880:Piperidines; D056564:Sirtuin 1; D037761:Sirtuins; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; C513312:Per2 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse; C495867:nicotinamide phosphoribosyltransferase, mouse; C470545:Sirt1 protein, mouse