An afferent vagal nerve pathway links hepatic PPARα activation to glucocorticoid-induced insulin resistance and hypertension
An afferent vagal nerve pathway links hepatic PPARα activation to glucocorticoid-induced insulin resistance and hypertension
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DOI：
10.1016/j.cmet.2006.12.010
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发表时间：
2007-02-01
期刊：
影响因子：
29
通讯作者：
Semenkovich, Clay F.
中科院分区：
文献类型：
--
作者：
Bernal-Mizrachi, Carlos;Liu Xiaozhong;Semenkovich, Clay F.
糖皮质激素过量会导致胰岛素抵抗和高血压。肝组织中PPARalpha（Ppara）的表达是糖皮质激素诱导的胰岛素抵抗所必需的。在这里，我们证明了迷走神经的传入纤维与肝脏Ppara表达的接口，以破坏血压和葡萄糖稳态响应糖皮质激素。选择性肝迷走神经切断术降低地塞米松处理的Ppara（+/+）小鼠的高血糖、高胰岛素血症、肝胰岛素抵抗、Ppara表达和磷酸烯醇式丙酮酸羧激酶（PEPCK）酶活性。选择性迷走神经切断术也降低了这些小鼠的血压、肾上腺素能张力、肾素活性和尿钠潴留。在非糖尿病、血压正常的地塞米松治疗的PPARa无效小鼠中，Ppara的肝脏重建增加了假手术动物的葡萄糖、胰岛素、肝脏PEPCK酶活性、血压和肾素活性，但没有增加肝迷走神经切断动物的葡萄糖、胰岛素、肝脏PEPCK酶活性。通过化学或手术手段破坏迷走神经传入纤维可防止糖皮质激素诱导的代谢紊乱。我们得出结论，肝Ppara表达和迷走神经传入通路之间的动态相互作用是必不可少的糖皮质激素诱导糖尿病和高血压。
Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPAR alpha (Ppara) is required for glucocorticoid-induced insulin resistance. Here we demonstrate that afferent fibers of the vagus nerve interface with hepatic Ppara expression to disrupt blood pressure and glucose homeostasis in response to glucocorticoids. Selective hepatic vagotomy decreased hyperglycemia, hyperinsulinemia, hepatic insulin resistance, Ppara expression, and phosphoenolpyruvate carboxykinase (PEPCK) enzyme activity in dexamethasone-treated Ppara(+/+) mice. Selective vagotomy also decreased blood pressure, adrenergic tone, renin activity, and urinary sodium retention in these mice. Hepatic reconstitution of Ppara in nondiabetic, normotensive dexamethasone-treated PPARa null mice increased glucose, insulin, hepatic PEPCK enzyme activity, blood pressure, and renin activity in sham-operated animals but not hepaticvagotomized animals. Disruption of vagal afferent fibers by chemical or surgical means prevented glucocorticoid-induced metabolic derangements. We conclude that a dynamic interaction between hepatic Ppara expression and a vagal afferent pathway is essential for glucocorticoid induction of diabetes and hypertension.