Science, doi:10.1126/science.1243417

The circadian clock regulates diverse facets of our behavior and physiology through tight transcriptional control of activators and repressors. Mice deficient in core clock components such as Clock have recently defined links to metabolic regulation, though the molecular machinery that ties the circadian clock to metabolic homeostasis is unclear. Peek et al. now report that mouse mutants in the activator loop of the clock (Clock and Bmal1) cause a decrease in fatty acid oxidation, oxygen consumption and NAD+ levels, indicating that mitochondrial oxidative reactions are under strict circadian control. As NAD+ levels are known to undergo cycling owing to circadian regulation of the biosynthesis enzyme, NAMPT, the authors hypothesized that the defective biosynthesis of NAD+ might be the primary cause for the loss of metabolic regulation. To test this hypothesis, they restored cellular NAD+ levels by providing nicotinamide mononucleotide, which elevated fatty acid oxidation and oxygen consumption to functional levels in intact animals and isolated mitochondria. NAD+ can promote fatty acid oxidation by regulating the activity of SIRT3, a mitochondrial deacetylase. Consistent with this, SIRT3 activity was diminished in Bmal1-deficient mice, resulting in increased acetylation of mitochondrial oxidative enzymes. Replenishing NAD+ levels in Bmal1-deficient mice could restore SIRT3 activity, resulting in the deacetylation and increased activity of fatty acid oxidation enzymes. These findings suggest that the circadian regulation of NAD+ levels is a crucial rheostat to control mitochondrial function and maintain metabolic homeostasis.