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

Saurabh Sahar,Maria Thereza Barbosa,Paolo Sassone-Corsi,Veronica Nin,Eduardo Nunes Chini

doi:10.18632/aging.100368

Saurabh Sahar, Maria Thereza Barbosa + Show 3 more

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https://doi.org/10.18632/aging.100368

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Abstract

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.

Highlights

Circadian rhythms occur with a periodicity of about 24 hours and regulate a wide array of metabolic and physiologic functions
Our present study shows that chronically elevated levels of NAD+ in CD38-null mice lead to modulation of the circadian clock illustrated by altered circadian behavior, clock gene expression and amino acid metabolism
We wanted to determine whether the differences in NAD+ levels between WT and CD38-KO mice may be due to a change in NADase activity

Summary

Introduction

Circadian rhythms occur with a periodicity of about 24 hours and regulate a wide array of metabolic and physiologic functions. CLOCK:BMAL1 heterodimers bind to promoters of clock controlled genes (CCGs) and regulate their expression. Some CCGs are special in the sense that they encode other core-clock regulators, such as Period and Cryptochrome genes, which negatively feedback on the clock machinery [1,2,3]. An additional novel transcriptional/enzymatic feedback loop that regulates the circadian clock has recently been uncovered [8,9]. The circadian clock controls the levels of NAD+ by regulating the expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis [8,9]. Tryptophan levels have been shown to oscillate in www.impactaging.com

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