Tissue-autonomous regulation of adipose expansion by core clock protein REVERBα. Tissue-autonomous regulation of adipose expansion by core clock protein REVERBα

The circadian clock coordinates energy metabolism, with REVERBα considered a dominant regulator of lipid metabolism. REVERBα is a core clock protein, which demonstrates robust rhythmic expression across metabolic tissues. Here, we explore its role in white adipose metabolism, and propose that REVERBα plays a key part in the response of adipose to obesity. Mice globally lacking Reverbα (Reverbα-/-) display adiposity, increased susceptibility to diet-induced obesity, and up-regulation of the lipogenic proteome in white adipose depots. When Reverbα is deleted selectively in adipose (ReverbαFlox2-6AdipoCre), however, we observe only modest phenotypic and transcriptomic changes in the basal state, with altered regulation of clock and extracellular matrix (ECM) pathways. Thus the adipose-autonomous actions of REVERBα are shaped by context. On high-fat diet challenge, ReverbαFlox2-6AdipoCre mice accumulate more adipose mass than littermate controls, and are spared obesity-related inflammation. Gene expression analysis reveals pathways of lipid handling to be up-regulated. These findings therefore highlight a critical role for REVERBα in the regulation of adipose tissue expansion. Further, when transcriptomic data is integrated with the REVERBα cistrome, we detect strong associations of REVERBα binding sites, not only with the clock and ECM targets de-repressed under normal conditions, but with the broad range of metabolic genes unmasked as REVERBα targets by obesity. Thus our data favour a new interpretation of REVERBα function, not as conferring rhythmicity to lipogenesis, but as buffering against lipogenic cues asynchronous to the normal temporal routine.