Nuclear receptors linking circadian rhythms and cardiometabolic control

Abstract

Many behavioral and physiological processes, including locomotor activity, blood pressure, body temperature, sleep (fasting)/wake (feeding) cycles, and metabolic regulation display diurnal rhythms. The biological clock ensures proper metabolic alignment of energy substrate availability and processing. Studies in animals and humans highlight a strong link between circadian disorders and altered metabolic responses and cardiovascular events. Shift work, for instance, increases the risk to develop metabolic abnormalities resembling the metabolic syndrome. Nuclear receptors have long been known as metabolic regulators. Several of them (ie, Rev-erbalpha, RORalpha, and peroxisome proliferation-activated receptors) are subjected to circadian variations and are integral components of molecular clock machinery. In turn, these nuclear receptors regulate downstream target genes in a circadian manner, acting to properly gate metabolic events to the appropriate circadian time window.

Figure 1

Circadian disruption may arise from genetic (clock gene mutations) or environmental (shiftwork,..) factors, and contributes to the development of behavioural and cardio-metabolic disorders.

Figure 2

The core clock machinery consists of a series of interlocked transcriptional/translational loops which generate and maintain circadian rhythms, and post-translational modifications (dashed lines) ensure the proper timing of the clock. Intracellular metabolism (through NAD+/SIRT1 and ATP/AMP-AMPK) and nutrients (through binding to nuclear receptors) impinge on the clock machinery (doted lines).