RNA sequencing of WT and ERRαγAd-/- brown adipose tissue treated with CL316,243

Adrenergic stimulation of brown adipose tissue (BAT) activates thermogenesis, by uncoupling oxidative phosphorylation and enabling high rates of substrate oxidation. Moreover, adrenergic stimulation signals to the nucleus, inducing gene expression changes that increase BAT thermogenic and oxidative capacity. The purpose of this study was to determine the role of two orphan nuclear receptors, ERRα and ERRγ, in adipose tissue function in response to adrenergic stimulation. Here we identify ERRα and ERRγ as collectively critical effectors of the adrenergic induced transcriptional program in BAT. Mice lacking adipose ERRs (ERRαγAd-/-) have diminished oxidative and thermogenic capacity, and become rapidly hypothermic when exposed to cold. Notably, the ability of the β3-adrenergic agonist CL316,243 to expand BAT oxidative and thermogenic capacity, increase energy expenditure, promote weight loss, and improve glucose tolerance is lost in ERRαγAd-/-. At the transcriptional level, RNA sequencing experiments show that the bulk of the response of BAT to CL316,243 (>80% of CL316,243-induced genes) relies on ERRs. These findings establish ERRα and ERRγ as essential BAT regulators that act coordinately to relay adrenergic signals and expand the capacity for thermogenesis and energy expenditure. WT and ERRαγAd-/- male mice were treated witht the β3-adrenergic agonist CL316,243 (1 mg/kg) or equivalent volume of PBS for 10 days. Mice were euthanized 24 hours after the last CL316,243 dose for BAT tissue collection. Total RNA was isolated from BAT and 3 samples from each condition were submitted for RNA sequencing (WT PBS, WT CL316,243, ERRαγAd-/- PBS, and ERRαγAd-/- CL316,243).