Lipolytic Products Activate Peroxisome Proliferator-activated Receptor (PPAR) α and δ in Brown Adipocytes to Match Fatty Acid Oxidation with Supply

beta-adrenergic receptors (beta-ARs) promote brown adipose tissue (BAT) thermogenesis by mobilizing fatty acids and inducing the expression of oxidative genes. beta-AR activation increases the expression of oxidative genes by elevating cAMP, but whether lipolytic products can modulate gene expression is not known. This study examined the role that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) plays in the induction of gene expression. Activation of brown adipocytes by beta-AR agonism or 8-bromo-cyclic AMP increased the expression of PGC1 alpha, PDK4, PPAR alpha, uncoupling protein 1 (UCP1), and neuron-derived orphan receptor-1 (NOR-1), and concurrent inhibition of HSL reduced the induction of PGC1 alpha, PDK4, PPAR alpha, and UCP1 but not NOR-1. Similar results were observed in the BAT of mice following pharmacological or genetic inhibition of HSL and in brown adipocytes with stable knockdown of ATGL. Conversely, treatments that increase endogenous fatty acids elevated the expression of oxidative genes. Pharmacological antagonism and siRNA knockdown indicate that PPAR alpha and PPAR delta modulate the induction of oxidative genes by beta-AR agonism. Using a live cell fluorescent reporter assay of PPAR activation, we demonstrated that ligands for PPAR alpha and -delta, but not PPAR gamma, were rapidly generated at the lipid droplet surface and could transcriptionally activate PPAR alpha and -delta. Knockdown of ATGL reduced cAMP-mediated induction of genes involved in fatty acid oxidation and oxidative phosphorylation. Consequently, ATGL knockdown reduced maximal oxidation of fatty acids, but not pyruvate, in response to cAMP stimulation. Overall, the results indicate that lipolytic products can activate PPAR alpha and PPAR delta in brown adipocytes, thereby expanding the oxidative capacity to match enhanced fatty acid supply.