Interconnections between circadian clocks and metabolism

Abstract

Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.

Figure 1. Intrinsic circadian clock machinery and metabolism.

Core circadian clock genes, including transcription activators and repressors, form an autoregulatory feedback loop present in most cells to regulate their circadian physiology. The figure summarizes the major metabolic functions regulated by core circadian clock genes in indicated tissues based on loss- and gain-of-function studies from genetically modified animal models.

Figure 2. Mechanisms of core clock component–specific regulation of target genes.

Core clock components independently, or forming protein complexes, bind to specific chromatin regions to directly regulate circadian gene expression (left). Each core clock component indirectly mediates circadian gene expression via downstream TFs (right). GR, glucocorticoid receptor; NRs, nuclear receptors.

Figure 3. Interactions between circadian rhythms and human physiology.

Light/dark cycles synchronize the intrinsic clock to a 24-hour cycle. In human physiology, alignment of wake/sleep cycles, eating patterns, and exercise schedule to certain circadian phases leads to beneficial metabolic outcomes, while misalignment exacerbates or causes metabolic disorders.