RNA sequencing of WT and ERRa?Ad-/- 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, ERRa and ERR?, in adipose tissue function in response to adrenergic stimulation. Here we identify ERRa and ERR? as collectively critical effectors of the adrenergic induced transcriptional program in BAT. Mice lacking adipose ERRs (ERRa?Ad-/-) have diminished oxidative and thermogenic capacity, and become rapidly hypothermic when exposed to cold. Notably, the ability of the ß3-adrenergic agonist CL316,243 to expand BAT oxidative and thermogenic capacity, increase energy expenditure, promote weight loss, and improve glucose tolerance is lost in ERRa?Ad-/-. 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 ERRa and ERR? as essential BAT regulators that act coordinately to relay adrenergic signals and expand the capacity for thermogenesis and energy expenditure. Overall design: WT and ERRa?Ad-/- male mice were treated witht the ß3-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, ERRa?Ad-/- PBS, and ERRa?Ad-/- CL316,243).