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.