The role of circadian clocks in metabolic disease

Abstract

The circadian clock is a highly conserved timing system, resonating physiological processes to 24-hour environmental cycles. Circadian misalignment is emerging as a risk factor of metabolic disease. The molecular clock resides in all metabolic tissues, the dysfunction of which is associated with perturbed energy metabolism. In this article, we will review current knowledge about molecular mechanisms of the circadian clock and the role of clocks in the physiology and pathophysiology of metabolic tissues.

Keywords: circadian clocks; metabolic disease; metabolism.

Figure 1

Architecture of the circadian timing system. Environmental cues, such as light, temperature, and food, reset the body clock through multiple pathways. The suprachiasmatic nucleus (SCN) of the brain is synchronized by light/dark cycles and orchestrates the daily oscillation of internal clocks in different tissues, such as liver, skeletal muscle, adipose tissue, and pancreas, through hormones and neurotransmitters. Environmental temperature cycles reset the body clock through cellular heat shock signaling and humoral/neural pathways. Food availability is also a potent time giver and entrains peripheral clocks through nutrient-sensing and hormonal pathways. The synchronization of different tissue clocks produce coordinated circadian rhythms of metabolic processes, including glucose metabolism, lipid metabolism, mitochondrial oxidation, and insulin secretion.

Figure 2

Molecular mechanisms of circadian expression of metabolic enzymes/regulators. The circadian clock regulates tissue metabolism mostly through expression of metabolic enzymes and regulators. Transcription factors of the circadian clock, such as REV-ERB, ROR and BMAL1/CLOCK can directly participate in the transcriptional control. Nutritional and hormonal signaling pathways, such as SREBP1c, cAMP/CREB, GRα, PPARα/PGC-1α/Lipin, are metabolic regulators. SREBP1c, glucocorticoid signaling, and the PPARα/PGC-1α/Lipin axis are under circadian control. CRY interacts with cAMP/CREB and GRα signaling to transmit temporal signals. In addition, the PER/REV-ERB axis and PGC-1α/ROR axis fine-tune the transcriptional network.