Nutrient sensing and the circadian clock

Abstract

The circadian system synchronizes behavioral and physiologic processes with daily changes in the external light-dark cycle, optimizing energetic cycles with the rising and setting of the sun. Molecular clocks are organized hierarchically, with neural clocks orchestrating the daily switch between periods of feeding and fasting, and peripheral clocks generating 24h oscillations of energy storage and utilization. Recent studies indicate that clocks respond to nutrient signals and that a high-fat diet influences the period of locomotor activity under free-running conditions, a core property of the clock. A major goal is to identify the molecular basis for the reciprocal relation between metabolic and circadian pathways. Here the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems is highlighted.

Figure 1. Circadian control of NAD⁺ and NAD⁺-dependent enzymes

The core circadian clock is composed of a feedback loop involving a series of activators (CLOCK/BMAL1) and repressors (CRYs/PERs) that generate ~24h rhythms of gene transcription. Targets of the circadian clock include genes involved in the production and utilization of nutrient metabolites, including the NAD⁺ biosynthetic enzyme NAMPT. NAD⁺ is an important cofactor for the metabolic regulators, SIRT1, SIRT3–5 and PARP1, which may mediate rhythms of oxidative metabolism.

Figure 2. Coordination of central and peripheral clocks by glucocorticoids

Light-derived cues stimulate hormonal signaling from hypothalamus/SCN to the adrenal cortex (via the autonomic nervous system (ANS) or via the pituitary gland), producing daily rhythms of glucocorticoid release. Glucocorticoids activate the glucocorticoid receptor in peripheral tissues, which ‘resets’ the molecular clocks and metabolic pathways.