Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β

Abstract

The nuclear receptors REV-ERB-α and REV-ERB-β are indispensible for the coordination of circadian rhythm and metabolism; mice without these nuclear receptors show disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. Metabolic processes need to run like clockwork to prevent disease. Core clock proteins drive these rhythms, and the nuclear receptors REV-ERB-α and REV-ERB-β have a central role in regulating the expression of clock genes. Solt et al. report the identification of potent synthetic REV-ERB agonists, termed SR9011 and SR9009, which can alter the circadian expression of core clock genes in the hypothalami of mice. This is shown to alter the expression of metabolic genes in liver, skeletal-muscle and adipose tissue, and results in increased energy expenditure by the mice. The REV-ERB agonists reduce fat mass in diet-induced obese mice and improve dyslipidaemia and hyperglycaemia. These results suggest that synthetic REV-ERB ligands are promising candidates for the treatment of metabolic diseases. Cho et al. present genetic evidence that REV-ERB-α and REV-ERB-β are indispensible for the coordination of circadian rhythm and metabolism. Mice without REV-ERBs show disrupted expression of clock and lipid homeostatic gene networks. They have altered circadian wheel-running behaviour and deregulated lipid metabolism. These data ally REV-ERB-α and REV-ERB-β with PER, CRY and other components of the principal feedback loop that drives circadian expression. The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK–BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-α and REV-ERB-β have been proposed to form an accessory feedback loop that contributes to clock function1,2, their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-α has been shown to regulate Bmal1 expression directly1,2, our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-α and REV-ERB-β genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-α and REV-ERB-β cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-α and Rev-erb-β function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-α and REV-ERB-β with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.