Deregulation of hepatic insulin sensitivity induced by central lipid infusion in rats is mediated by nitric oxide

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

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10 Scopus citations

Abstract

Background: Deregulation of hypothalamic fatty acid sensing lead to hepatic insulin-resistance which may partly contribute to further impairment of glucose homeostasis. Methodology: We 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 Findings: Lipids 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/Significance: We 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.

Original languageEnglish (US)
Article numbere6649
JournalPloS one
Volume4
Issue number8
DOIs
StatePublished - Aug 14 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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