Deregulation of hepatic insulin sensitivity induced by central lipid infusion in rats is mediated by nitric oxide
PLoS ONE. 2009-08-14; 4(8): e6649
DOI: 10.1371/journal.pone.0006649
Lire sur PubMed
1. PLoS One. 2009 Aug 14;4(8):e6649. doi: 10.1371/journal.pone.0006649.
Deregulation of hepatic insulin sensitivity induced by central lipid infusion in
rats is mediated by nitric oxide.
Marsollier N(1), Kassis N, Mezghenna K, Soty M, Fioramonti X, Lacombe A, Joly A,
Pillot B, Zitoun C, Vilar J, Mithieux G, Gross R, Lajoix AD, Routh V, Magnan C,
Cruciani-Guglielmacci C.
Author information:
(1)CNRS-Université Paris Diderot, Paris, France.
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.
DOI: 10.1371/journal.pone.0006649
PMCID: PMC2721417
PMID: 19680547 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.