Nicolas Marsollier

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.

L’assimilation des lipides au niveau de l’intestin grêle active des mécanismes qui permettent de réguler la digestion des nutriments et le comportement alimentaire. Cela passe par l’activation du nerf vague et des sécrétions hormonales, qui induisent la terminaison des repas, module lamotilité gastrique et la sécrétion de sels biliaires. Cette revue porte sur des phospholipides produits dans l’entérocyte, qui constituent une nouvelle voie de signalisation intervenant dans la régulation desmécanismes de satiété, et informe l’organisme sur la nature et la quantité de lipides ingérés. Deux espèces de phospholipides se distinguent: les N-acyl-éthanolamines (NAE), et les N-acyl-phosphatidyl-éthanolamines (NAPE). Les NAE ont une action essentiellement périphérique alors que les NAPE agissent préférentiellement au niveau du système nerveux central (SNC). Leurs actions diffèrent selon la chaîne acylée associée et sont dépendantes du peroxisome proliferatoractivated receptor alpha (PPARα), du transporteur d’acide gras CD36 et du récepteur aux vanilloïdes TRPV1. Les études de leurs effets révèlent une capacité satiétogène puissante qui en fait des cibles thérapeutiques potentielles dans la lutte contre les troubles du comportement alimentaires. Lipid assimilation in the small intestine activates mechanisms that regulate nutrient digestion and eating behaviour. These are related to nervous activation of the vagus nerve and hormonal secretions, which cause people to finish meals as well as causing gastric motility and bile salt secretion. This review concerns enterocyte phospholipids (fatty acid amides), a new pathway that contributes to the regulation of food intake and informs the organism about the nature and quantity of lipids ingested. The roles of two types are mainly described in literature: N-acyl-ethanolamide (NAE), and N-acyl-phosphatidyl-ethanolamide (NAPE). NAE action is mostly peripheral, whereas NAPE mostly take effect in the central nervous system. The effects of fatty acid amides differ according to the fatty acid they link, and are dependent on peroxisome proliferator-activated receptor alpha (PPARα), fatty acid transporters CD36, and vanilloidreceptors TRPV1. Studies on their effects reveal a strong satiating capacity and highlight a new potential therapeutic target to prevent food behaviour disorders and over-eating.