Journal
CELL METABOLISM
Volume 5, Issue 2, Pages 91-102Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2006.12.010
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Funding
- NHLBI NIH HHS [P50 HL083762-010001, HL58427, P50 HL083762, R01 HL058427] Funding Source: Medline
- NIA NIH HHS [AG20091, R01 AG020091] Funding Source: Medline
- NIDDK NIH HHS [P30 DK056341-06, P30 DK056341-05S29002, P30 DK020579, P30 DK056341, DK20579, P30 DK056341-05S2, P60 DK020579] Funding Source: Medline
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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.
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