Journal Article

Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists

Takahashi, Joseph S., Cameron, Michael D., Noel, Romain, Liu, Jin, Burris, Thomas P., Yoo, Seung-Hee, Hughes, Travis, Lundasen, Thomas, Butler, Andrew A., Shin, Youseung, Kamenecka, Theodore M., Banerjee, Subhashis, Solt, Laura A., Wang, Yongjun, Kojetin, Douglas J.

2012

Overview

Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases. Synthetic REV-ERB agonists can alter the circadian expression of core clock genes in the hypothalami of mice, which changes the expression of metabolic genes in liver, skeletal muscle and adipose tissue, and results in increased energy expenditure. Adjusting the metabolic clock 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/436/108 / 631/378/1385/2640 / 631/443/319/1642/393 / Adipose tissue / Adipose Tissue - drug effects / Adipose Tissue - metabolism / Animals / Biological and medical sciences / Biological Clocks - drug effects / Biological Clocks - genetics / Biological Clocks - physiology / Cell culture / Circadian rhythm / Circadian Rhythm - drug effects / Circadian Rhythm - genetics / Circadian Rhythm - physiology / Circadian rhythms / Disease Models, Animal / Drug dosages / Energy Metabolism - drug effects / HEK293 Cells / Humanities and Social Sciences / Humans / Hypothalamus - drug effects / Hypothalamus - metabolism / Ligands / Liver - drug effects / Liver - metabolism / Medical sciences / Metabolic disorders / Metabolome - drug effects / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Miscellaneous / multidisciplinary / Muscle, Skeletal - drug effects / Muscle, Skeletal - metabolism / Nuclear Receptor Subfamily 1, Group D, Member 1 - antagonists & inhibitors / Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism / Obesity - chemically induced / Obesity - drug therapy / Obesity - metabolism / Pharmacology. Drug treatments / Plasma / Pyrrolidines - pharmacology / Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors / Receptors, Cytoplasmic and Nuclear - metabolism / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Thiophenes - pharmacology