Pioglitazone prevents obesity-related airway hyperreactivity and neuronal M2 receptor dysfunction.
Pioglitazone prevents obesity-related airway hyperreactivity and neuronal M2 receptor dysfunction.
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吡格列酮可预防肥胖相关的气道高反应性和神经元 M2 受体功能障碍。
DOI：
10.1152/ajplung.00567.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Nie,Zhenying
中科院分区：
文献类型：
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作者：
Proskocil,BeckyJ;Fryer,AllisonD;Jacoby,DavidB;Nie,Zhenying
与肥胖相关的哮喘通常表现出比非肥胖相关的哮喘更严重的症状，而且对目前的治疗反应很差。胰岛素抵抗和高胰岛素血症在肥胖症中都很常见。我们已经证明，胰岛素增加通过导致神经元M2毒碱受体功能障碍来介导饮食诱导的肥胖大鼠的气道高反应性，而M2受体功能障碍通常会抑制副交感神经释放乙酰胆碱。用链脲佐菌素降低胰岛素可预防呼吸道高反应性和M2受体功能障碍。本研究的目的是探讨降糖药物吡格列酮是否能预防肥胖大鼠的气道高反应性和M2受体功能障碍。雄性大鼠喂饲低脂或高脂饲料，每日灌胃给予吡格列酮或PBS。记录体重、体脂、空腹胰岛素、对电刺激迷走神经和雾化乙酰甲胆碱所致的支气管收缩和心动过缓。用M受体激动剂匹罗卡品测定M2受体功能。高脂饮食的大鼠增强了对迷走神经刺激和功能障碍的神经元M2受体的气道反应性，而对乙酰甲胆碱的气道反应性没有影响。吡格列酮可降低空腹胰岛素，预防气道高反应性和M2受体功能障碍，但不改变肺泡巨噬细胞炎性细胞因子mRNA的表达。高脂饮食加和不加吡格列酮对胰岛素受体mRNA的表达有组织特异性影响。综上所述，吡格列酮可预防肥胖大鼠迷走神经介导的气道高反应性，保护神经元型M2受体功能。
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 M2muscarinic receptor dysfunction, which normally inhibits acetylcholine release from parasympathetic nerves. Decreasing insulin with streptozotocin prevented airway hyperreactivity and M2receptor dysfunction. The objective of the present study was to investigate whether pioglitazone, a hypoglycemic drug, prevents airway hyperreactivity and M2receptor 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 M2receptor function. Rats on a high-fat diet had potentiated airway responsiveness to vagal stimulation and dysfunctional neuronal M2receptors, whereas airway responsiveness to methacholine was unaffected. Pioglitazone reduced fasting insulin and prevented airway hyperresponsiveness and M2receptor 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 M2muscarinic receptor function in obese rats.