Bernal-Mizrachi Carlos, Xiaozhong Liu, Yin Li, Knutsen Russell H, Howard Michael J, Arends Joop J A, Desantis Pascual, Coleman Trey, Semenkovich Clay F
Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Cell Metab. 2007 Feb;5(2):91-102. doi: 10.1016/j.cmet.2006.12.010.
Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARalpha (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 PPARalpha null mice increased glucose, insulin, hepatic PEPCK enzyme activity, blood pressure, and renin activity in sham-operated animals but not hepatic-vagotomized 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.
糖皮质激素过量会导致胰岛素抵抗和高血压。糖皮质激素诱导的胰岛素抵抗需要肝脏中过氧化物酶体增殖物激活受体α（PPARα，Ppara）的表达。在此，我们证明迷走神经的传入纤维与肝脏Ppara表达相互作用，以响应糖皮质激素而破坏血压和葡萄糖稳态。选择性肝迷走神经切断术可降低地塞米松处理的Ppara(+/+)小鼠的高血糖、高胰岛素血症、肝脏胰岛素抵抗、Ppara表达以及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还可降低这些小鼠的血压、肾上腺素能张力、肾素活性以及尿钠潴留。在非糖尿病、血压正常的地塞米松处理的PPARα基因敲除小鼠中，肝脏重建Ppara可增加假手术动物的血糖、胰岛素、肝脏PEPCK酶活性、血压和肾素活性，但对肝迷走神经切断术动物无效。通过化学或手术方法破坏迷走神经传入纤维可预防糖皮质激素诱导的代谢紊乱。我们得出结论，肝脏Ppara表达与迷走神经传入途径之间的动态相互作用对于糖皮质激素诱导糖尿病和高血压至关重要。
