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

TLDR

Rev‑erbα is a nuclear receptor that modulates circadian rhythm and metabolism, yet its influence has been viewed as modest, positioning it as a secondary regulator of the cell‑autonomous clock. The authors aimed to determine the combined effect of deleting Rev‑erbα and its close paralog Rev‑erbβ on circadian timing and hepatic lipid metabolism. Loss of both Rev‑erbs rendered mouse fibroblasts arrhythmic, derepressed metabolic and clock genes in liver, induced marked hepatic steatosis, and demonstrated that these receptors act as major, collaboratively regulated drivers of circadian and metabolic homeostasis.

Abstract

The nuclear receptor Rev-erbα 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 Rev-erbα together with closely related Rev-erbβ 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-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, 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.