Circadian Fluctuations In NAD+ Levels Fine-Tune The Circadian Oscillation

Recently, studies in mammalian cells suggest that NAD+ levels are regulated in a circadian rhythm. This rhythm is due to the salvage pathway, a two-step reaction that converts nicotinamide to nicotinamide mononucleotide (NMN) to NAD+

Circadian Fluctuations In NAD+ Levels Fine-Tune The Circadian Oscillation

Circadian fluctuations in NAD+ levels fine-tune the circadian oscillation

Circadian fluctuations in NAD+ levels fine-tune the circadian oscillation of the CLOCK-BMAL1 complex via Sirt1 Recently, studies in mammalian cells suggest that NAD+ levels are regulated in a circadian rhythm. This rhythm is due to the salvage pathway, a two-step reaction that converts nicotinamide to nicotinamide mononucleotide (NMN) to NAD+ (210, 228, 270). The two enzymes responsible for catalyzing these reactions are nicotinamide phophoribosyltransferase (NAMPT) and NMN adenylytransferases (NMNAT) (95, 273). What makes this scenario interesting for the understanding of sirtuins' physiology is that SIRT1 utilizes NAD+ in its biochemical reaction to generate nicotinamide. Thus NAMPT, NMNAT, and SIRT1 close a loop in a biochemical cascade from nicotinamide down to NMN, NAD+, and finally nicotinamide (228, 270).

It is intuitive to hypothesize that if NAD+ fluctuates according to the circadian cycle, then SIRT1 activity should vary as well, because it is linked to NAD+ levels. Several reports shed light on these mechanisms, showing that SIRT1 interacts with CLOCK to generate a protein complex (SIRT1-CLOCK). SIRT1 was shown to bind and deacetylate the CLOCK complex, leading to degradation of the complex and inactivation of circadian gene transcription (2, 39). Thus SIRT1 deacetylase activity affects the CLOCK complex by regulating acetyl residues, driving degradation of the complex. Additionally, the CLOCK-BMAL1 complex was shown to bind to the NAMPT promoter where it upregulates NAMPT expression (40, 47). Increases in NAMPT levels contribute to enhance the levels of NAD+, which in turn activates SIRT1. SIRT1 subsequently deacetylates the CLOCK complex and releases it from the DNA, decreasing the transcription of NAMPT. With less NAMPT, levels of NAD+ decrease and, consequently, so does SIRT1 activity. This NAMPT-SIRT1 loop acts to fine-tune the circadian oscillation of the CLOCK-BMAL1 complex, linking metabolism variances to the circadian rhythm (40, 47).

Ruben Nogueiras, Kirk M. Habegger, Nilika Chaudhary, Brian Finan, Alexander S. Banks, Marcelo O. Dietrich, Tamas L. Horvath, David A. Sinclair, Paul T. Pfluger, and Matthias H. Tschöop Physiol Rev. 2012 Jul; 92(3): 1479–1514.