Regulation of metabolism: the circadian clock dictates the time

Abstract

Circadian rhythms occur with a periodicity of approximately 24h and regulate a wide array of metabolic and physiologic functions. Accumulating epidemiological and genetic evidence indicates that disruption of circadian rhythms can be directly linked to many pathological conditions, including sleep disorders, depression, metabolic syndrome and cancer. Intriguingly, several molecular gears constituting the clock machinery have been found to establish functional interplays with regulators of cellular metabolism. Although the circadian clock regulates multiple metabolic pathways, metabolite availability and feeding behavior can in turn regulate the circadian clock. An in-depth understanding of this reciprocal regulation of circadian rhythms and cellular metabolism may provide insights into the development of therapeutic intervention against specific metabolic disorders.

Figure 1. Regulation of metabolism by the circadian clock

Peripheral clocks, such as the one in liver, are regulated by the master clock present in the suprachiasmatic nucleus (SCN). The liver clock can regulate multiple metabolic pathways by various mechanisms. These mechanisms include regulation of rate-limiting steps, control of metabolite levels, interaction with nutrient sensors, and modulation of nuclear receptors.

Figure 2. Interplay between regulators of circadian clock and metabolism

CLOCK and BMAL1 regulate circadian gene expression by binding to E-box elements within the promoters of clock controlled genes (CCGs). Some of the CCGs are regulators of metabolic pathways (e.g. Pepck, Glut2, Hmgcr), while some can influence metabolite levels (e.g. Nampt, Alas1). Nutrient sensors AMPK and SIRT1 are regulated in a circadian manner, and they can modulate circadian rhythms and metabolism by post-translational modifications of key regulators.