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.