Circadian disruption, clock genes, and metabolic health

Abstract

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health-related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.

Figure 1. Circadian control of molecular core clock gene signaling and physiologic regulation.

The central, peripheral, and molecular clocks and the physiological processes under circadian control. The circadian clock (purple) in the suprachiasmatic nucleus (SCN) of the brain sets peripheral clocks in individual organs and tissue types (light green) via signals including circulating hormones, metabolites, the sympathetic nervous system, and body temperature. Within the cells of the SCN and each organ/tissue type, each cell contains transcription-translation feedback loops, the molecular clocks that drive circadian rhythms. These molecular clocks regulate the transcription of thousands of CCGs and direct the daily oscillatory expression of thousands of COGs and additional transcription factors that mediate the timing of myriad physiological processes as represented in the molecular clock pathway within cells.

Figure 2. Foundational evidence of core clock gene regulation and metabolic health in animal models and human studies.

Summary of the current state of knowledge regarding circadian disruption, CCG expression, and the development of adverse metabolic health–related pathologies.