Adipocyte REVERBα dictates adipose tissue expansion during obesity
Louise Hunter A., Pelekanou CE., Barron NJ., Northeast RC., Adamson A., Downton P., Cornfield T., Cunningham PS., Hodson L., Loudon ASI., Unwin RD., Iqbal M., Ray DW., Bechtold DA.
<jats:title>ABSTRACT</jats:title><jats:p>The circadian clock component REVERBα is considered a dominant regulator of lipid metabolism, with global <jats:italic>Reverbα</jats:italic> deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (<jats:italic>Reverbα<jats:sup>Flox2-6</jats:sup>Adipo<jats:sup>Cre</jats:sup></jats:italic>), and transcriptional profiling demonstrates that, under basal conditions, direct targets of REVERBα regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, <jats:italic>Reverbα<jats:sup>Flox2-6</jats:sup>Adipo<jats:sup>Cre</jats:sup></jats:italic> mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT REVERBα cistrome with differential gene expression reveals broad control of metabolic processes by REVERBα which is unmasked in the obese state. Adipocyte REVERBα does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, REVERBα action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.</jats:p>