Integration of Circadian Rhythm and Metabolism through Coactivator PGC-1alpha

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Abstract Most living organisms exhibit behavioral and physiological rhythms, including sleep, activity, blood pressure as well as lipid and carbohydrate metabolism. This diurnal oscillation is regulated by circadian clock, which responds to light and feeding cycles. Perturbed clock function has been implicated in sleep disorders and it is associated with increased cardiovascular risk. Disruption of clock function in rodents leads to obesity and impaired glucose homeostasis, suggesting that energy homeostasis is linked to biological timing systems. The physiological and molecular mechanisms that integrate clock and energy metabolism, however, remain poorly defined. We have previously demonstrated that PGC-1¿, a transcriptional coactivator that regulates several major aspects of energy metabolism, including hepatic gluconeogenesis, fatty acid ¿-oxidation, and mitochondrial oxidative metabolism, also controls clock gene expression. Mice deficient in PGC-1¿ have aberrant circadian rhythms of locomotor activity, body temperature, metabolic rate, and diurnal patterns of metabolic gene expression. Based on these findings, we hypothesize that the integration of clock and metabolism is achieved through reciprocal crosstalk between circadian pacemaker and metabolic regulatory networks. We will explore this hypothesis by evaluating the role of PGC-1¿ in tissue- autonomous integration of clock and metabolism. We will also explore molecular components involved in the crosstalk between the circadian pacemaker and PGC-1¿. Finally, we will investigate novel mechanisms through which the PGC-1¿ regulatory network controls circadian metabolic rhythms. How circadian pacemaker and energy metabolism are integrated in individual tissues remains a fundamental question. Our study has the potential to elucidate key molecular components that link the circadian timing system to energy homeostasis, and to gain insights into pathogenic mechanisms of metabolic and cardiovascular diseases.