Clocks, metabolism, and the epigenome

Abstract

Many behaviors and physiological activities in living organisms display circadian rhythms, allowing the organisms to anticipate and prepare for the diurnal changes in the living environment. In this way, metabolic processes are aligned with the periodic environmental changes and behavioral cycles, such as the sleep/wake and fasting/feeding cycles. Disturbances of this alignment significantly increase the risk of metabolic diseases. Meanwhile, the circadian clock receives signals from the environment and feedback from metabolic pathways, and adjusts its activity and function. Growing evidence connects the circadian clock with epigenomic regulators. Here we review the recent advances in understanding the crosstalk between the circadian clock and energy metabolism through epigenomic programming and transcriptional regulation.

Figure 1. The basic clock machinery consists of negative transcriptional-translational feedback loops

In the first loop, BMAL1/CLOCK drives Per/Cry transcription, while PER/CRY binds and inhibits transcriptional activity of BMAL1/CLOCK. In the second loop, BMAL1/CLOCK drives REV-ERB expression, which in turn represses Bmal1 transcription. Both loops are essential for maintaining circadian rhythm. In addition, post-translational modification, as shown for PER/CRY and REV-ERB, is also important in regulating clock activity. The core clock machinery can drive rhythmic behavioral and physiological activities, such as metabolism.

Figure 2. Overview of the interplays between environment, circadian clocks and metabolism

The circadian clock in the cells comprising metabolic organs, such as liver, functions as an epigenomic programmer and controls metabolic outputs. This autonomous apparatus is regulated by the central clock in the SCN and by food intake via hormones and nutrients/metabolites. Both the central clock and food availability contributes to the temporal regulation of food intake.

Figure 3. The core clock machinery drives rhythmic metabolic activities and receives feedback from intracellular metabolites

BMAL1/CLOCK and REV-ERB drive rhythmic metabolic outputs, including NAD⁺ and heme biosynthesis, while intracellular NAD⁺ and heme feedback on the clock through their sensors, SIRT1 and REV-ERB, respectively. Intracelluar AMP levels regulates the circadian clock through activation of AMPK and degradation of PER and CRY. The core clock also drives many metabolic pathways in different tissues, which also contribute to the intracellular metabolite pool and metabolic state.