Keeping up with the nicotinamides: NADP(H), the forgotten circadian cofactor that keeps metabolic time

The hierarchical relationship between the core circadian clock of the suprachiasmatic nucleus and peripheral clocks throughout the body is tightly regulated. Nicotinamide adenine dinucleotide phosphate (NADP(H)) is a rhythmic cofactor used in hundreds of metabolic reactions. The cellular NADP(H) pool is not only regulated by several clock-controlled enzymes, but also responsive to peripheral “zeitgebers” such as food intake and oxidative stress. This positions NADP(H) as a potential harbinger between core and peripheral metabolic rhythms. While discussion in recent years has focused on its unphosphorylated counterpart, NAD(H), this review aims to highlight the roles of NADP(H) in circadian metabolism. This review discusses the multilayered regulation of cellular NADP(H), how the total pool size, redox ratio, and rhythmicity of NADP(H) impact core and peripheral rhythms, and how disruption of its rhythmic regulation can lead to metabolic disease.