Circadian clocks and energy metabolism

Abstract

Circadian clocks orchestrate behavioral and physiological processes in a time-of-day dependent manner. The network of clock-controlled genes is intimately interconnected with metabolic regulatory circuits. Circadian clocks rhythmically regulate the expression and activity of key metabolic players, which in turn feed back on the circadian machinery on the transcriptional and post-transcriptional level. Mutations of clock genes are often associated with metabolic defects, especially in lipid and glucose metabolism. Accumulating data suggest that the reciprocal coordination of circadian and metabolic pathways is crucial for cellular homeostasis and the health of the organism.

Fig. 1

The mammalian molecular clock with major metabolic regulatory points. The main positive limb of mammalian molecular clock is formed by the transcription activator BMAL1/CLOCK, which binds to E-boxes and drives circadian gene expression. The activity of BMAL1/CLOCK is inhibited by PERs and CRYs in a negative feedback loop. Metabolic signals that are conveyed through AMPK and SIRT1 regulate the levels of PER/CRY complexes. SIRT1 deacetylates PER2 and thereby promotes its degradation, whereas AMPK enhances CK1ε activity, which leads to phosphorylation and subsequent degradation of PER2. In addition, phosphorylation of CRY1 by AMPK enhances its degradation. AMPK also activates SIRT1 by increasing cellular NAD⁺ levels, adding a further critical metabolic feedback regulation [184]. In addition, transcription factors such as RORs, REV-ERBs and PPARs affect the phase and amplitude of the oscillation of Bmal1 expression. Genome-wide ChIPseq analyses suggest that REV-ERBs, RORs and PPARs regulate in addition to Bmal1 also other CCGs

Fig. 2

Regulation of cholesterol biosynthesis by the circadian clock. Expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis, is regulated by the circadian clock. Transcription of Hmgcr is facilitated by SREBPs, which are expressed as inactive precursors. Proteolytic processing is required for the activation of SREBPs. This process is regulated by INSIG1, INSIG2 and SCAP. Srebf1, Insig2 and Scap transcriptions are circadian with different phases. In addition to regulation by SREBPs, REV-ERBα and BMAL1 binding sites are also found in the Hmgcr. The regulation results in evening-specific expression of Hmgcr and cholesterol synthesis. In a negative feedback, cholesterol inhibits Hmgcr expression by promoting retention of the SCAP/SREBP complex in the ER. Sine curves indicate the circadian phases of the corresponding components