[PDF][PDF] An afferent vagal nerve pathway links hepatic PPARα activation to glucocorticoid-induced insulin resistance and hypertension

C Bernal-Mizrachi, L Xiaozhong, L Yin, RH Knutsen… - Cell metabolism, 2007 - cell.com
C Bernal-Mizrachi, L Xiaozhong, L Yin, RH Knutsen, MJ Howard, JJA Arends, P DeSantis…
Cell metabolism, 2007cell.com
Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of
PPARα (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 …
Summary
Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARα (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 PPARα 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.
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