[Background and Objectives]: Obesity is associated with a low-grade inflammation in adipose tissue that contributes to defects in the critical nodes of insulin signaling in peripheral tissues. We investigated the impact of saturated (palmitate, P) and unsaturated (oleate, O) fatty acid (FA) overload in stress signaling and insulin signaling in hepatocytes focusing on the effects elicited by direct FA stimulation or through macrophage/kupffer activation. In addition, the effect of several lipid species derived from FA on hepatic insulin signaling was evaluated. [Methods]: Mouse hepatocytes were treated with O, P or the combination of both. Raw 264.7 rnacrophages or kupffer cells were stimulated with O or P and after 24 h mRNA levels of pro-inflammatory cytokines were analyzed and the condition medium (CM) was added to hepatocytes. Activation of STAT3, stress kinases, ER stress markers and insulin signaling was assessed. Lipidomic analysis was performed in CM from O or P-loaded Raw 264.7 cells. Lipid species were used individually to treat macrophages or hepatocytes and evaluate insulin signaling. [Results and Conclusions]: P, but not 0, activated stress kinases in both hepatocytes and macrophages. Whereas insulin signaling was reduced in hepatocytes directly treated with P or CM of P-stimulated macrophages/kupffer cells, insulin hypersensitivity was observed in hepatocytes treated with O or CM of O-stimulated macrophages/kupffer cells. Moreover, O prevented the direct negative effects of P on insulin signaling in hepatocytes. Interestingly, CM of O-treated rnacrophages showed reduced LTB4 and 14,15 DHET levels compared to the CM of P treatment. These lipid species reverted the effects of O on hepatic insulin signaling. In conclusion, O and P elicit opposite cross-talks on hepatic insulin signaling either directly or through macrophage activation. Whereas P interferes at early steps (IFUIRSl) through the activation of stress kinases, O elicits insulin sensitizing effects and prevents the deleterious effects of P possibly by the reduction in LTB4 and 14,15 DHET lipid mediators. We are evaluating the rnechanims responsible of the insulin sensitizing effects of O in hepatocytes.

Resumen del póster presentado al XII International Symposium on Insulin Receptors and Insulin Action: "New Opportunities for the Prevention and Treatment of Diabetes in the XXI Century", celebrado en Barcelona (España) del 7 al 9 de noviembre de 2013.

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