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

Abstract

Synchronizing rhythms of behavior and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERBα and REV-ERBβ play 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 behavior 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 dyslipidemia and hyperglycemia. These results suggest that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may hold utility in the treatment of sleep disorders as well as metabolic diseases.

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Rev-erb intervient aussi dans le développement du tissu adipeux et la synthèse des acides biliaires et du glucose [37]. Le traitement de souris avec des ligands synthétiques de Rev-erb/ induit une perte de poids et l'amélioration de la sensibilité à l'insuline [38]. ROR régule le méta-bolisme des lipides et la synthèse des acides biliaires parallèlement à son action sur Bmal1 [39].…”

Implications du gène d’horlogeReverbαdans l’obésité

“…deux gènes sont invalidés ont une stéa-tose hépatique sévère, sont hyperglycémiques et quasiment arythmiques, même en présence d'un cycle de lumière et d'obscurité [7][8][9] (➜). Nos résultats, ainsi que ces autres travaux, ouvrent la voie au développe-ment de nouvelles stratégies thérapeutiques ciblant les voies de signalisation associées aux protéines REVERB pour limiter ou traiter les désordres circadiens et leurs consé-quences sur l'homéostasie énergétique, comme l'illustre d'ailleurs une autre publication récente [10]. ◊ When our metabolic health depends on our internal clocks…”

The effects of chronic carbon monoxide treatment on diet-induced obesity and Rev-erb-alpha target gene expression in adipose tissue

“…Although heme has been identified as the ligand for Rev-erb-α [15,16], evidence suggests the Drosophila orthologue to Rev-erb-α binds CO and represses gene expression [10]. Whether or not the expression of Rev-erb-α targets is altered in tissues following CO treatment is not known, although a Rev-erb agonist has been shown to promote weight loss and suppress PGC-1α mRNA expression, an established target of Rev-erb-α [14].…”

“…Rev-erb-α is a ligand regulated transcription factor that acts as a transcriptional repressor [11,12] regulating circadian rhythms and metabolism [13,14]. Although heme has been identified as the ligand for Rev-erb-α [15,16], evidence suggests the Drosophila orthologue to Rev-erb-α binds CO and represses gene expression [10].…”