The nuclear receptor ERRγ maintains innate brown fat thermogenic capacity. Mus musculus

Brown adipose tissue (BAT) plays a critical role in thermogenesis. This high-energy consuming process makes BAT an attractive therapeutic target for combating obesity. In response to cold, transcription factors, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mediate the adaptive changes in the expression of oxidative and thermogenic genes in BAT. However, even in the absence of cold, BAT exhibits high expression of these genes relative to white adipose tissue (WAT). Here, we identify estrogen-related receptor gamma (ERRγ) as a critical factor that controls the expression of key metabolic genes in BAT under basal conditions. ERRγ is highly expressed in BAT versus WAT, yet is not transcriptionally induced by cold, suggesting it plays an important role in innate basal BAT function rather than in the adaptive response to cold. Indeed, RNA-sequencing from mice lacking ERRγ specifically in adipose tissue (ERRγASKO mice) revealed minimal changes in gene expression under chronic cold conditions. However, at thermoneutrality there was marked down-regulation of genes involved in fatty acid oxidation and thermogenesis. As a result, under thermoneutral conditions, ERRγASKO mice develop decreased BAT mass, with enlarged lipid droplets, and exhibit impaired thermogenic capacity. This defective BAT results in an inability to survive upon acute exposure to cold, revealing that ERRγ is critical for priming BAT for thermogenesis.