Circadian mechanisms in bioenergetics and cell metabolism

Circadian clocks are biologic oscillators present in all photosensitive species that produce 24-h cycles in the transcription of rate-limiting metabolic enzymes in anticipation of the light-dark cycle. In mammals, the clock drives energetic cycles to maintain physiologic constancy during the daily switch in behavioral (sleep/wake) and nutritional (fasting/feeding) states. A molecular connection between circadian clocks and tissue metabolism was first established with the discovery that 24-h transcriptional rhythms are cell-autonomous and selfsustained in cultured fibroblasts, and that clocks are present in most tissues and comprise a robust temporal network throughout the body. A central question remains: how do circadian transcriptional programs integrate physiologic systems within individual cells of the intact animal and how does the ensemble of local clocks align temporal harmonics in the organism with the environment? Our approach to studies of metabolic regulation by the molecular clock began with analyses of metabolic pathologies in circadian mutant animals, experiments that first became possible with the cloning of the clock genes in the late 1990s. A paradox in our early studies was that the effects of circadian clock disruption were both nutrient-and time-dependent, so that, under fed conditions, animals exhibited diabetes whereas during fasting, they decompensated and died. Application of a broad range of tissue-specific genetic and biochemical approaches has now begun to provide mechanistic insight into the circadian control of metabolism.