Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD ⁺ Biosynthesis

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 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.

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

“…Additional evidence for clock genes being sensors of the cellular metabolic state comes from studies showing that the DNA binding activity of CLOCK/BMAL1 heterodimers is dependent on the redox state of the cell (Rutter=et alK, 2001). The molecular cascade underlying this phenomenon involves the rate limiting enzyme in the NAD synthesis, NAMPT, and the histone deacetylase SIRT1, a suppressor of CLOCK/BMAL1-mediated transcription (Nakahata= et alK, 2009;Ramsey=et alK, 2009). Interestingly -and similar to what was shown for heme -k~ãéí transcription itself is clock controlled, providing a mechanism for a gating of the sensitivity of the clock that allows a time-dependent response of peripheral circadian clocks to redox state signalling (Fig.…”

The role of clock genes and rhythmicity in the liver

“…2; Asher et al, 2008;Nakahata et al, 2008). Furthermore, cellular NAD + levels cycle with a period of 24 h (Nakahata et al, 2009;Ramsey et al, 2009). This circadian variation of NAD + may be regulated via the rate-limiting enzyme of mammalian NAD + biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) that is under circadian control.…”

The daily rhythm of mice

“…Since the circadian clock regulates the ratelimiting enzyme of mammalian nicotinamide adenine dinucleotide (NAD + ) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT, see Fig. 1), and as a consequence causes levels of NAD + to display circadian oscillations [70,71], the clock affects at least those metabolic pathways that depend on NAD + or NADH, respectively. Another proposed interaction between metabolic cycles and the circadian clock appears to be an enzyme that responds to nutrient availability, adenosine monophosphate-activated protein kinase (AMPK).…”