E-MTAB-8840
Tissue-autonomous regulation of adipose expansion by core clock protein REVERBa
The circadian clock coordinates energy metabolism, with REVERBa considered a dominant regulator of lipid metabolism. REVERBa 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 REVERBa plays a key part in the response of adipose to obesity. Mice globally lacking Reverba (Reverba-/-) display adiposity, increased susceptibility to diet-induced obesity, and up-regulation of the lipogenic proteome in white adipose depots. When Reverba is deleted selectively in adipose (ReverbaFlox2-6AdipoCre), 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 REVERBa are shaped by context. On high-fat diet challenge, ReverbaFlox2-6AdipoCre 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 REVERBa in the regulation of adipose tissue expansion. Further, when transcriptomic data is integrated with the REVERBa cistrome, we detect strong associations of REVERBa 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 REVERBa targets by obesity. Thus our data favour a new interpretation of REVERBa function, not as conferring rhythmicity to lipogenesis, but as buffering against lipogenic cues asynchronous to the normal temporal routine.
The circadian clock coordinates energy metabolism, with REVERBa considered a dominant regulator of lipid metabolism. REVERBa 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 REVERBa plays a key part in the response of adipose to obesity. Mice globally lacking Reverba (Reverba-/-) display adiposity, increased susceptibility to diet-induced obesity, and up-regulation of the lipogenic proteome in white adipose depots. When Reverba is deleted selectively in adipose (ReverbaFlox2-6AdipoCre), 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 REVERBa are shaped by context. On high-fat diet challenge, ReverbaFlox2-6AdipoCre 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 REVERBa in the regulation of adipose tissue expansion. Further, when transcriptomic data is integrated with the REVERBa cistrome, we detect strong associations of REVERBa 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 REVERBa targets by obesity. Thus our data favour a new interpretation of REVERBa function, not as conferring rhythmicity to lipogenesis, but as buffering against lipogenic cues asynchronous to the normal temporal routine.