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

• Published in: PloS one Vol. 4; no. 8; p. e6649
• Main Authors: Marsollier, Nicolas, Kassis, Nadim, Mezghenna, Karima, Soty, Maud, Fioramonti, Xavier, Lacombe, Amélie, Joly, Aurélie, Pillot, Bruno, Zitoun, Carine, Vilar, José, Mithieux, Gilles, Gross, René, Lajoix, Anne-Dominique, Routh, Vanessa, Magnan, Christophe, Cruciani-Guglielmacci, Céline
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.08.2009; Public Library of Science (PLoS)
• Subjects: Acetylcholinesterase; Active control; Animals; Arginine; Brain; Carotid artery; Deregulation; Diabetes therapy; Dimers; Endocrinology and metabolism; Enzyme Inhibitors - pharmacology; Fatty acids; Fatty liver; Feeding Behavior; Glucose; Glucose - metabolism; Homeostasis; Human health and pathology; Hypothalamus; Hypothalamus (ventromedial); Hypothalamus - enzymology; Inhibitors; Injection; Insulin; Insulin Resistance; Life Sciences; Lipids; Liver; Liver - physiology; Monomethyl-L-arginine; Monounsaturated fatty acids; Neurons; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric-oxide synthase; Nutrition/Obesity; Oleic acid; Oleic Acid - administration & dosage; Parasympathetic nervous system; Physiology/Endocrinology; Physiology/Integrative Physiology; Rats; Rodents; Sensitivity; Triglycerides; France; United States > US; New Jersey
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0006649

Deregulation of hypothalamic fatty acid sensing lead to hepatic insulin-resistance which may partly contribute to further impairment of glucose homeostasis. 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). 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). 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.