The Time of Metabolism: NAD+, SIRT1, and the Circadian Clock

scale, considering that as many 10% of cellular transcripts oscillate in a circadian manner. CLOCK, a transcription factorcrucial for circadian function, has intrinsic histone acetyltransferase activity and operates within a large nuclear complex with other chromatin remodelers. CLOCK directs the cyclic acetylation of the histone H3 and of its own partner BMAL1. A search for the histone deacetylase (HDAC) that counterbalanced CLOCK activity revealed that SIRT1, a nicotinamide adenine dinucleotide (NAD þ )-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of several metabolic processes and was found to interact with CLOCK and to be recruited to circadian promoters in a cyclic manner. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link among energy balance, chromatin remodeling, and circadian physiology. Figuring out how metabolism is modulated byenvironmental and nutritional cues is a task of great conceptual and pharmacological interest. In this respect, an element that occupies a critical position is time. A remarkable array of fundamental physiological functions are circa