Figure 4.

Circadian control and influence of energy sensing pathways

Mitochondrial function, substrate utilization, insulin sensitivity, and glycemic control exhibit diurnal rhythms that are influenced by a variety of factors including energetic stressors such as diet, exercise, and metabolic disease, as well as intrinsic clocks. The molecular circadian clock is composed of transcriptional activators, circadian locomotor output cycles kaput (CLOCK), and brain and muscle ARNTL-like protein 1 (BMAL1), and their target genes period (PER), cryptochrome (CRY), NR1D1 (which encodes REV-ERBα) and DBP, which rhythmically accumulate and form a repressor complex that interacts with CLOCK and BMAL1 to inhibit transcriptional activity. Energetic stressors influence the circadian program and metabolism. AMPK-mediated phosphorylation of CRY and PER promotes their destabilization and degradation, while mTOR activation induces CRY1 expression. PER2 inhibits mTOR complex activity via the tuberous sclerosis complex 1. HIF1α regulates PER2 transcription and interacts with BMAL1 at the chromatin level. CRY1 reduces HIF1α half-life by interacting with its basic-helix-loop-helix domain.