Deregulation of Hepatic Insulin Sensitivity Induced by Central Lipid Infusion in Rats Is Mediated by Nitric Oxide

Nicolas Marsollier,Vanessa Routh,Aurélie Joly,Karima Mezghenna,Bruno Pillot,Anne-Dominique Lajoix,Christophe Magnan,Maud Soty,Céline Cruciani-Guglielmacci,Xavier Fioramonti,Gilles Mithieux,Carine Zitoun,José Vilar,René Gross,Nadim Kassis,Amélie Lacombe,Carlo Polidori

doi:10.1371/journal.pone.0006649

Abstract

BackgroundDeregulation of hypothalamic fatty acid sensing lead to hepatic insulin-resistance which may partly contribute to further impairment of glucose homeostasis.MethodologyWe investigated here whether hypothalamic nitric oxide (NO) could mediate deleterious peripheral effect of central lipid overload. Thus we infused rats for 24 hours into carotid artery towards brain, either with heparinized triglyceride emulsion (Intralipid, IL) or heparinized saline (control rats).Principal FindingsLipids infusion led to hepatic insulin-resistance partly related to a decreased parasympathetic activity in the liver assessed by an increased acetylcholinesterase activity. Hypothalamic nitric oxide synthases (NOS) activities were significantly increased in IL rats, as the catalytically active neuronal NOS (nNOS) dimers compared to controls. This was related to a decrease in expression of protein inhibitor of nNOS (PIN). Effect of IL infusion on deregulated hepatic insulin-sensitivity was reversed by carotid injection of non selective NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) and also by a selective inhibitor of the nNOS isoform, 7-Nitro-Indazole (7-Ni). In addition, NO donor injection (L-arginine and SNP) within carotid in control rats mimicked lipid effects onto impaired hepatic insulin sensitivity. In parallel we showed that cultured VMH neurons produce NO in response to fatty acid (oleic acid).Conclusions/SignificanceWe conclude that cerebral fatty acid overload induces an enhancement of nNOS activity within hypothalamus which is, at least in part, responsible fatty acid increased hepatic glucose production.

Highlights

Metabolic Syndrome is a constellation of disturbance where insulin resistance is considered as a key factor in the onset of disorders [1]
Since inducible NOS (iNOS) produces larger amount of nitric oxide (NO) than constitutive NO synthase (NOS) [20], NO generation by the latter appears to be more adapted in cell signaling. neuronal NOS (nNOS) activity is partly regulated by protein inhibitor of nNOS (PIN), which has been identified in rat brain [21]
In this study we showed that central lipid overload led to increased hypothalamic NOS activity and to both hepatic insulin resistance and increased glucose-induced insulin secretion (GIIS)

Summary

Introduction

Metabolic Syndrome is a constellation of disturbance where insulin resistance is considered as a key factor in the onset of disorders [1]. It has been shown that short term intracerebroventricular infusion of oleic acid reduced both food intake and hepatic glucose production [13] Besides this acute effect of hypothalamic FA sensing, it appeared that central FA overload -which could occur during metabolic diseases- deregulate such sensing, leading to impaired CNS control of glucose homeostasis, insulin secretion and sensitivity [14]. We hypothesized that the hypothalamic nitric oxide (NO) production mediates the central effects of FA It has been shown in other tissues such as pancreatic beta cell that lipids exposure activates NO pathway in physiological and physiopathological conditions [17,18]. Deregulation of hypothalamic fatty acid sensing lead to hepatic insulin-resistance which may partly contribute to further impairment of glucose homeostasis

Methods

Results

Conclusion