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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 M<jats:sub>2<\/jats:sub> muscarinic receptor dysfunction, which normally inhibits acetylcholine release from parasympathetic nerves. Decreasing insulin with streptozotocin prevented airway hyperreactivity and M<jats:sub>2<\/jats:sub> receptor dysfunction. The objective of the present study was to investigate whether pioglitazone, a hypoglycemic drug, prevents airway hyperreactivity and M<jats:sub>2<\/jats:sub> receptor dysfunction in obese rats. 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 M<jats:sub>2<\/jats:sub> receptor function. Rats on a high-fat diet had potentiated airway responsiveness to vagal stimulation and dysfunctional neuronal M<jats:sub>2<\/jats:sub> receptors, whereas airway responsiveness to methacholine was unaffected. Pioglitazone reduced fasting insulin and prevented airway hyperresponsiveness and M<jats:sub>2<\/jats:sub> 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. In conclusion, pioglitazone prevents vagally mediated airway hyperreactivity and protects neuronal M<jats:sub>2<\/jats:sub> muscarinic receptor function in obese rats. <\/jats:p>","DOI":"10.1152\/ajplung.00567.2020","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T13:07:08Z","timestamp":1621429628000},"page":"L236-L247","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Pioglitazone prevents obesity-related airway hyperreactivity and neuronal M<sub>2<\/sub> receptor dysfunction"],"prefix":"10.1152","volume":"321","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7803-6447","authenticated-orcid":true,"given":"Becky J.","family":"Proskocil","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison 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