Hyperinsulinemia promotes heterologous desensitization of β2 adrenergic receptor in airway smooth muscle in obesity

Rui Xu, Raghavender Reddy Gopireddy, Yudi Wu, Lei Wu, Xiang Tao, Ji Shao, Wenxin Wang, Li Li, Aleksandra Jovanovic, Bing Xu, Nicolas J. Kenyon, Quan Lu, Yang K. Xiang, Qin Fu

Research output: Contribution to journalArticle

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 β2AR-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 β2AR-Gi-ERK1/2 cascade. Both acute and chronic pharmacological inhibition of PDE4 effectively reversed impaired β2AR-mediated ASM relaxation in an obesity mouse model induced by a high fat diet. Collectively, these findings reveal that cross talk between insulin and β2AR signaling promotes ASM β2AR 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 β2AR desensitization in ASM. Moreover, PDE4 inhibitors may be used as efficacious therapeutic agents for asthma in obese and diabetic subjects.

Original languageEnglish (US)
JournalFASEB Journal
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • asthma
  • obesity
  • phosphodiesterase 4
  • β-adrenergic receptor agonist

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Xu, R., Gopireddy, R. R., Wu, Y., Wu, L., Tao, X., Shao, J., Wang, W., Li, L., Jovanovic, A., Xu, B., Kenyon, N. J., Lu, Q., Xiang, Y. K., & Fu, Q. (Accepted/In press). Hyperinsulinemia promotes heterologous desensitization of β2 adrenergic receptor in airway smooth muscle in obesity. FASEB Journal. https://doi.org/10.1096/fj.201800688RR