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An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension.

ABSTRACT: 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.

SUBMITTER: Bernal-Mizrachi C

PROVIDER: S-EPMC1899170 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension.

Bernal-Mizrachi Carlos C Xiaozhong Liu L Yin Li L Knutsen Russell H RH Howard Michael J MJ Arends Joop J A JJ Desantis Pascual P Coleman Trey T Semenkovich Clay F CF

Cell metabolism 20070201 2

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 ...[more]

PMID: 17276352

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Project description:GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic β cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.

Project description:BackgroundIncreasing number of studies provide evidence that the vagus nerve stimulation (VNS) dampens inflammation in peripheral visceral organs. However, the effects of afferent fibers of the vagus nerve (AFVN) on anti-inflammation have not been clearly defined. Here, we investigate whether AFVN are involved in VNS-mediated regulation of hepatic production of proinflammatory cytokines.MethodsAn animal model of hepatitis was generated by intraperitoneal (i.p.) injection of concanavalin A (ConA) into rats, and electrical stimulation was given to the hepatic branch of the vagus nerve. AFVN activity was regulated by administration of capsaicin (CAP) or AP-5/CNQX and the vagotomy at the hepatic branch of the vagus nerve (hVNX). mRNA and protein expression in target tissues was analyzed by RT-PCR, real-time PCR, western blotting and immunofluorescence staining. Hepatic immune cells were analyzed by flow cytometry.ResultsTNF-α, IL-1β, and IL-6 mRNAs and proteins that were induced by ConA in the liver macrophages were significantly reduced by the electrical stimulation of the hepatic branch of the vagus nerve (hVNS). Alanine transaminase (ALT) and aspartate transaminase (AST) levels in serum and the number of hepatic CD4+ and CD8+ T cells were increased by ConA injection and downregulated by hVNS. CAP treatment deteriorated transient receptor potential vanilloid 1 (TRPV1)-positive neurons and increased caspase-3 signals in nodose ganglion (NG) neurons. Concomitantly, CAP suppressed choline acetyltransferase (ChAT) expression that was induced by hVNS in DMV neurons of ConA-injected animals. Furthermore, hVNS-mediated downregulation of TNF-α, IL-1β, and IL-6 expression was hampered by CAP treatment and similarly regulated by hVNX and AP-5/CNQX inhibition of vagal feedback loop pathway in the brainstem. hVNS elevated the levels of α7 nicotinic acetylcholine receptors (α7 nAChR) and phospho-STAT3 (Tyr705; pY-STAT3) in the liver, and inhibition of AFVN activity by CAP, AP-5/CNQX and hVNX or the pharmacological blockade of hepatic α7 nAChR decreased STAT3 phosphorylation.ConclusionsOur data indicate that the activity of AFVN contributes to hepatic anti-inflammatory responses mediated by hVNS in ConA model of hepatitis in rats.

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An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension.

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An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension.

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