Abstract
Insulin resistance plays an important role in obesity-associated asthma exacerbations. Using a murine model of allergic airway inflammation, we evaluated the insulin signaling transmission in lungs of obese compared with lean mice. We further evaluated the effects of the polyphenol resveratrol in the pulmonary insulin signaling. In lean mice, insulin stimulation significantly increased phosphorylations of AKT, insulin receptor substrate 1 (IRS-1) and insulin receptor β (IRβ) in lung tissue and isolated bronchi (p < 0.05), which were impaired in obese group. Instead, obese mice displayed increased tyrosine nitrations of AKT, IRβ and IRS-1 (p < 0.05). Two-week therapy of obese mice with resveratrol (100 mg/kg/day) restored insulin-stimulated AKT, IRS-1 and IRβ phosphorylations, and simultaneously blunted the tyrosine nitration of these proteins. Additionally, the c-Jun N-terminal kinase (JNK) and inhibitor of NF-κB Kinase (IκK) phosphorylations were significantly increased in obese group, an effect normalized by resveratrol. In separate experiments, the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (20 mg/kg/day, three weeks) mimicked the protective effects exerted by resveratrol in lungs of obese mice. Lungs of obese mice display nitrosative-associated impairment of insulin signaling, which is reversed by resveratrol. Polyphenols may be putative drugs to attenuate asthma exacerbations in obese individuals.
Highlights
Insulin resistance plays an important role in obesity-associated asthma exacerbations
The higher prevalence of insulin resistance in obese and asthmatic patients compared with obese non-asthmatics has suggested that insulin resistance plays a role in obesity-related asthma exacerbation
Our present findings clearly indicate impaired insulin signaling in the lungs of obese mice, as evaluated by the reduced insulin-stimulated phosphorylation of AKT, insulin receptor substrate 1 (IRS-1) and IR1β, along with increased phosphorylation of Jun N-terminal kinase (JNK) and inhibitor of NF-κB Kinase (IκK)
Summary
Insulin resistance plays an important role in obesity-associated asthma exacerbations. Insulin stimulation significantly increased phosphorylations of AKT, insulin receptor substrate 1 (IRS-1) and insulin receptor β (IRβ) in lung tissue and isolated bronchi (p < 0.05), which were impaired in obese group. Two-week therapy of obese mice with resveratrol (100 mg/kg/day) restored insulin-stimulated AKT, IRS-1 and IRβ phosphorylations, and simultaneously blunted the tyrosine nitration of these proteins. Attenuation of the insulin resistance of obese mice by the anti-hyperglycemic drug metformin attenuates the eosinophilic airway inflammation and iNOS-derived NO concentrations to the levels of lean asthmatic group, suggesting that systemic insulin resistance play a role in asthma exacerbation in obesity conditions[9]. Prolonged administration of high-fat diet-fed mice with the iNOS inhibitor aminoguanidine fully restored the obesity-induced insulin resistance and significantly attenuated the eosinophil infiltration in the lung tissue[9]. A greater understanding of the role of eosinophils in glucose homeostasis and in patients with asthma is warranted to provide more accurate phenotype-driven therapy[16]
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