The molecular clock as a metabolic rheostat

Abstract

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 behavioural (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 self-sustained in most tissues and comprise a robust temporal network throughout the body. A major window in understanding how the clock is coupled to metabolism was opened with discovery of metabolic syndrome pathologies in multi-tissue circadian mutant mice including susceptibility to diet-induced obesity and diabetes. Using conditional transgenesis and dynamic metabolic testing, we have pinpointed tissue-specific roles of the clock in energy and glucose homeostasis, with our most detailed understanding of this process in endocrine pancreas. Here, we review evidence for dynamic regulation of insulin secretion and oxidative metabolic functions by the clock transcription pathway to regulate homeostatic responses to feeding and fasting. These studies indicate that clock transcription is a determinant of tissue function and provide a reference for understanding molecular pathologies linking circadian desynchrony to metabolic disease.