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

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.

SUBMITTER: Sahar S

PROVIDER: S-EPMC3184980 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Sahar Saurabh S Nin Veronica V Barbosa Maria Thereza MT Chini Eduardo Nunes EN Sassone-Corsi Paolo P

Aging 20110801 8

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 mic ...[more]

PMID: 21937766

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Project description:Circadian rhythms are internal processes repeating approximately every 24 hours in living organisms. The dominant circadian pacemaker is synchronized to the environmental light-dark cycle. Other circadian pacemakers, which can have noncanonical circadian mechanisms, are revealed by arousing stimuli, such as scheduled feeding, palatable meals and running wheel access, or methamphetamine administration. Organisms also have ultradian rhythms, which have periods shorter than circadian rhythms. However, the biological mechanism, origin, and functional significance of ultradian rhythms are not well-elucidated. The dominant circadian rhythm often masks ultradian rhythms; therefore, we disabled the canonical circadian clock of mice by knocking out Per1/2/3 genes, where Per1 and Per2 are essential components of the mammalian light-sensitive circadian mechanism. Furthermore, we recorded wheel-running activity every minute under constant darkness for 272 days. We then investigated rhythmic components in the absence of external influences, applying unique multiscale time-resolved methods to analyze the oscillatory dynamics with time-varying frequencies. We found four rhythmic components with periods of ∼17 h, ∼8 h, ∼4 h, and ∼20 min. When the ∼17-h rhythm was prominent, the ∼8-h rhythm was of low amplitude. This phenomenon occurred periodically approximately every 2-3 weeks. We found that the ∼4-h and ∼20-min rhythms were harmonics of the ∼8-h rhythm. Coupling analysis of the ridge-extracted instantaneous frequencies revealed strong and stable phase coupling from the slower oscillations (∼17, ∼8, and ∼4 h) to the faster oscillations (∼20 min), and weak and less stable phase coupling in the reverse direction and between the slower oscillations. Together, this study elucidated the relationship between the oscillators in the absence of the canonical circadian clock, which is critical for understanding their functional significance. These studies are essential as disruption of circadian rhythms contributes to diseases, such as cancer and obesity, as well as mood disorders.

Dataset Information

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

Publications

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

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