Intracellular fatty acids suppress β-adrenergic induction of PKA-targeted gene expression in white adipocytes

Mottillo EP, Granneman JG. Intracellular fatty acids suppress beta-adrenergic induction of PKA-targeted gene expression in white adipocytes. Am J Physiol Endocrinol Metab 301: E122-E131, 2011. First published April 19, 2011; doi: 10.1152/ajpendo.00039.2011 doi: 10.1152/ajpendo.00039.2011.-beta-Adrenergic receptor (beta-AR) activation elevates cAMP levels in fat cells and triggers both metabolic and transcriptional responses; however, the potential interactions between these pathways are poorly understood. This study investigated whether lipolysis affects beta-AR-mediated gene expression in adipocytes. Acute beta(3)-adrenergic receptor (beta(3)-AR) stimulation with CL 316,243 (CL) increased expression of PKA-targeted genes PCG-1 alpha, UCP1, and NOR-1 in mouse white fat. Limiting lipolysis via inhibition of hormone-sensitive lipase (HSL), a direct target of PKA, sharply potentiated CL induction of PCG-1 alpha, UCP1, and NOR-1. CL also induced greater expression of PKA-targeted genes in white fat of HSL-null mice compared with wild-type littermates, further indicating that HSL activity limits PKA-mediated gene expression. Inhibiting HSL in 3T3-L1 adipocytes also potentiated the induction of PGC-1 alpha, UCP1, and NOR-1 by beta-AR activation, as did siRNA knockdown of adipose triglyceride lipase, the rate-limiting enzyme for lipolysis. Conversely, treatments that promote intracellular fatty acid accumulation suppressed induction of PGC-1 alpha and UCP1 through beta-AR stimulation. Analysis of beta-adrenergic signaling indicated that excessive intracellular fatty acid production inhibits adenylyl cyclase activity and thereby reduces PKA signaling to the nucleus. Lastly, partially limiting lipolysis by inhibition of HSL increased the induction of oxidative gene expression and mitochondrial electron transport chain activity in white adipose tissue and facilitated fat loss in mice treated for 5 days with CL. Overall, our results demonstrate that fatty acids limit the upregulation of beta-AR-responsive genes in white adipocytes and suggest that limiting lipolysis may be a novel means of enhancing beta-AR signaling.