RESUMEN
ß-Adrenergic receptor (ß-AR) agonists are the most common clinical bronchodilators for asthma. Obesity influences asthma severity and may impair response to ß-AR agonists. Previous studies show that in obese mice, hyperinsulinemia plays a crucial role in ß-AR desensitization in the heart. We therefore investigated whether insulin promotes ß-AR desensitization in airway smooth muscle (ASM) and compromises airway relaxation responsiveness to ß-AR agonists. We found that human ASM cells and mouse airway tissues exposed to insulin exhibit impaired ß2 AR-induced cAMP accumulation and airway relaxation. This impaired relaxation is associated with insulin-induced phosphorylation and expression of phosphodiesterase 4D (PDE4D) through transactivation of a G protein-coupled receptor kinase 2 (GRK2)-dependent ß2 AR-Gi -ERK1/2 cascade. Both acute and chronic pharmacological inhibition of PDE4 effectively reversed impaired ß2 AR-mediated ASM relaxation in an obesity mouse model induced by a high fat diet. Collectively, these findings reveal that cross talk between insulin and ß2 AR signaling promotes ASM ß2 AR desensitization in obesity through upregulation of PDE4D phosphorylation and expression. Our results identify a novel pathway of asthma pathogenesis in patients with obesity/metabolic syndrome, in which the GRK2-mediated signaling can be a potential therapeutic modality to prevent or treat ß2 AR desensitization in ASM. Moreover, PDE4 inhibitors may be used as efficacious therapeutic agents for asthma in obese and diabetic subjects.