Deregulation of hepatic insulin sensitivity induced by central lipid infusion in rats is mediated by nitric oxide.
BACKGROUND
Deregulation of hypothalamic fatty acid sensing lead to hepatic insulin-resistance which may partly contribute to further impairment of glucose homeostasis.


METHODS
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).


RESULTS
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
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.
Marsollier
Nicolas
N
CNRS-Université Paris Diderot, Paris, France. nicolas.marsollier@univ-paris-diderot.fr
Kassis
Nadim
N
Mezghenna
Karima
K
Soty
Maud
M
Fioramonti
Xavier
X
Lacombe
Amélie
A
Joly
Aurélie
A
Pillot
Bruno
B
Zitoun
Carine
C
Vilar
José
J
Mithieux
Gilles
G
Gross
René
R
Lajoix
Anne-Dominique
AD
Routh
Vanessa
V
Magnan
Christophe
C
Cruciani-Guglielmacci
Céline
C
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005247:Feeding Behavior; D005947:Glucose / Q000378:metabolism; D007031:Hypothalamus / Q000201:enzymology; D007333:Insulin Resistance; D008099:Liver / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D019301:Oleic Acid / Q000008:administration & dosage*; D051381:Rats
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D019301:Oleic Acid; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D005947:Glucose
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