Pioglitazone prevents obesity-related airway hyperreactivity and neuronal M2 receptor dysfunction

Rationale: Obesity-related asthma often presents with more severe symptoms than non-obesity-related asthma and responds poorly to current treatments. Both insulin resistance and hyperinsulinemia are common in obesity. We have shown that increased insulin mediates airway hyperreactivity in diet-induced obese rats by causing neuronal M2 muscarinic receptor dysfunction, which normally inhibits acetylcholine release from parasympathetic nerves. Decreasing insulin with streptozotocin prevented airway hyperreactivity and M2 receptor dysfunction. Objective: To investigate whether pioglitazone, a hypoglycemic drug, prevents airway hyperreactivity and M2 receptor dysfunction in obese rats. Methods & Measurements: Male rats fed a low- or high-fat diet were treated with pioglitazone or PBS by daily gavage. Body weight, body fat, fasting insulin and bronchoconstriction and bradycardia in response to electrical stimulation of vagus nerves and to aerosolized methacholine were recorded. Pilocarpine, a muscarinic receptor agonist, was used to measure M2 receptor function. Results: Rats on a high-fat diet had potentiated airway responsiveness to vagal stimulation and dysfunctional neuronal M2 receptors, while airway responsiveness to methacholine was unaffected. Pioglitazone reduced fasting insulin and prevented airway hyperresponsiveness and M2 receptor dysfunction, but did not change inflammatory cytokine mRNA expression in alveolar macrophages. High-fat diet, with and without pioglitazone, had tissue-specific effects on insulin receptor mRNA expression. Conclusion: Pioglitazone prevents vagally mediated airway hyperreactivity and protects neuronal M2 muscarinic receptor function in obese rats.