Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

Abstract

The nuclear receptor Rev-erba regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Reverba together with closely related Rev-erbb has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbb mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erba, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.

Circadian regulation of lipid metabolism

“…Similarly, mice with loss of function of Cry1 and Cry2 show impaired glucose tolerance, as well as higher circulating levels of corticosterone (78) . As might be expected, animals with loss of both REV-ERBα and REV-ERBβ function exhibit profound deficits in lipid metabolism, including a marked increase in liver TAG, severe hepatic steatosis, and hyperglycaemia (51,52) . In contrast, mice with an intragenic deletion in the coding region of RORα are protected against diet-induced obesity and show reduced adiposity (79,80) .…”

“…For example, thousands of DNAbinding sites in mouse liver are rhythmically occupied by BMAL1, including genes involved in sterol and TAG metabolic pathways (49,50) . Similarly, the circadian cistromes for REV-ERBα, nuclear receptor corepressor and histone deacetylase 3 overlap extensively and are enriched for genes involved in lipid metabolism (51)(52)(53) . Circadian rhythms in genome-wide occupancy for BMAL1, REV-ERBα and REV-ERBβ show strong overlap for metabolic pathways and transcriptional regulators in the liver (52) , and similar findings have been reported for other core clock proteins (BMAL1, CLOCK, NPAS2, PER1, PER2, CRY1 and CRY2) (54) .…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Rev-erb et Rev-erb corégulent les gènes de la lipogenèse de façon circadienne permettant d'assurer l'homéostasie lipidique. Leur délétion spécifiquement dans le foie conduit à l'apparition d'une stéatose hépatique [35,36]. Rev-erb intervient aussi dans le développement du tissu adipeux et la synthèse des acides biliaires et du glucose [37].…”

Implications du gène d’horlogeReverbαdans l’obésité

“…Cette altération métabolique est très largement amplifiée par un régime hyperlipidique ( histogrammes de droite) (d'après [6]). 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].…”