The increase in unsaturated fatty acids is related with an anti-inflammatory profile in the hypothalamus of non-diabetic IRS2-deficient mice

Resumen del trabajo presentado al 19th European Congress of Endocrinology (ECE), celebrado en Lisboa (Portugal) del 20 al 23 de mayo de 2017.[Background]: IRS2-deficient (IRS2-/-) mice are considered a good model to analyze the development of diabetes as some of them present an increase in glycemia comparable to that observed in diabetes onset in humans, whereas a high proportion of these mice do not develop diabetes. Energy homeostasis regulation by the hypothalamus can be disturbed by an inflammatory environment, which predisposes an individual to the onset of diabetes. Saturated fatty acids induce hypothalamic dysfunction, whereas unsaturated fatty acids mediate severa! anti-inflammatory actions. [Objectives]: Our aim was to determine the pattern of fatty acids in the hypothalamus of non-diabetic IRS2-/- (ND) and diabetic IRS2-/- (D) mice and its possible assodation with hypothalamic inflammation. [Methods]: We studied 18 male mice including controls, ND and D mice. We analyzed enzymes involved in the generation of NADPH, fatty acid synthesis and regulation of energy homeostasis by western blotting and pro- and anti-inflammatory chemokines/cytokines by multiplexed bead immunoassay. Metabolomic studies were performed by proton nuclear magnetic resonance (H-NMR) after extraction of hypothalamic metabolites in organic solvents. [Results]: Malic enzyme was increased in ND mice and fatty acid synthase in D and ND, with a greater increase in ND. Acetyl·CoA carboxylase was inhibited and AMPK activated in D mice, with no changes in ND mice. Among the studied chemokines/cytokines, monocyte chemoattractant protein-1, fractalkine and interleukin (IL)-2 were increased in D and IL-4 en ND mice. Metabolomic studies revealed an increase in the levels of ω3-fatty acids, phosphatydil-ethanolamine, linolenic acid and MUFA plus PUFA in the hypothalamus of ND m ice with respect to controls. A negative correlation of analyzed metabolites with fractalkine and a positive correlation with IL-4 was observed. [Conclusion]: The favorable hypothalamic lipid profile suggests a beneficia! role against hypothalamic inflammation in non-diabetic IRS2-/- mice.Peer Reviewe