Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD⁺ oscillation

The Intracellular levels of nicotinamide adenine dinucleotide (NAD⁺) are rhythmic and controlled by the circadian clock. However, whether NAD⁺ oscillation in turn contributes to circadian physiology is not fully understood. To address this question we analyzed mice mutated for the NAD+ hydrolase CD38. We found that rhythmicity of NAD⁺ was altered in the CD38-deficient mice. The high, chronic levels of NAD⁺ results in several anomalies in circadian behavior and metabolism. CD38-null mice display a shortened period length of locomotor activity and alteration in the rest-activity rhythm. Several clock genes and, interestingly, genes involved in amino acid metabolism were deregulated in CD38-null livers. Metabolomic analysis identified alterations in the circadian levels of several amino acids, specifically tryptophan levels were reduced in the CD38-null mice at a circadian time paralleling with elevated NAD⁺ levels. Thus, CD38 contributes to behavioral and metabolic circadian rhythms and altered NAD⁺ levels influence the circadian clock.