Fig. 1.

By activating SIRT1, NAD⁺ conjoins two feedback loops necessary for cross talk between the circadian clock and metabolite production. The levels of the metabolite NAD⁺ were shown to oscillate in a circadian manner in various cell types, suggesting that it could determine the cyclic function of NAD⁺-dependent enzymes, such as SIRT1. It has been shown that the salvage pathway is critical to regulate intracellular NAD⁺ levels. After the conversion of NAM into NAM mononucleotide (NMN) by NAMPT, NMN is further modified into NAD⁺ by the NAM mononucleotide adenylyl transferases (Nmnat-1, -2, and -3). Although NAM inhibits SIRT1 activity, NAD⁺-activated SIRT1 feeds back into the NAD⁺ salvage pathway by directly regulating Nampt gene expression in a CLOCK:BMAL1-dependent manner (28). By this mechanism, NAD⁺ conjoins the two feedback loops, contributing to the fine tuning necessary for achieving energy balance.