Hyperinsulinemia promotes heterologous desensitization of β ₂ adrenergic receptor in airway smooth muscle in obesity

Abstract

β-Adrenergic receptor (β-AR) agonists are the most common clinical bronchodilators for asthma. Obesity influences asthma severity and may impair response to β-AR agonists. Previous studies show that in obese mice, hyperinsulinemia plays a crucial role in β-AR desensitization in the heart. We therefore investigated whether insulin promotes β-AR desensitization in airway smooth muscle (ASM) and compromises airway relaxation responsiveness to β-AR agonists. We found that human ASM cells and mouse airway tissues exposed to insulin exhibit impaired β₂ 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 β₂ AR-G_i -ERK1/2 cascade. Both acute and chronic pharmacological inhibition of PDE4 effectively reversed impaired β₂ 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 β₂ AR signaling promotes ASM β₂ 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 β₂ AR desensitization in ASM. Moreover, PDE4 inhibitors may be used as efficacious therapeutic agents for asthma in obese and diabetic subjects.