Novel Function of Rev-erbα in Promoting Brown Adipogenesis

Brown adipose tissue is a major thermogenic organ that plays a key role in maintenance of body temperature and whole-body energy homeostasis. Rev-erb alpha, a ligand-dependent nuclear receptor and transcription repressor of the molecular clock, has been implicated in the regulation of adipogenesis. However, whether Rev-erb alpha participates in brown fat formation is not known. Here we show that Rev-erb alpha is a key regulator of brown adipose tissue development by promoting brown adipogenesis. Genetic ablation of Rev-erb alpha in mice severely impairs embryonic and neonatal brown fat formation accompanied by loss of brown identity. This defect is due to a cell-autonomous function of Rev-erb alpha in brown adipocyte lineage commitment and terminal differentiation, as demonstrated by genetic loss-and gain-of-function studies in mesenchymal precursors and brown preadipocytes. Moreover, pharmacological activation of Rev-erb alpha activity promotes, whereas its inhibition suppresses brown adipocyte differentiation. Mechanistic investigations reveal that Rev-erb alpha represses key components of the TGF-beta cascade, an inhibitory pathway of brown fat development. Collectively, our findings delineate a novel role of Rev-erb alpha in driving brown adipocyte development, and provide experimental evidence that pharmacological interventions of Rev-erb alpha may offer new avenues for the treatment of obesity and related metabolic disorders.