Solinas, Giovanni and Naugler, Willscott and Galimi, Francesco and Lee, Myung-Shik and Karin, Michael (2006) Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proceedings of The National Academy of Sciences, Vol. 103 (44), p. 16454-16459. eISSN 1091-6490. Article.
JNKs are attractive targets for treatment of obesity and type-2 diabetes. A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic β-cells. In the latter, palmitic acid treatment inhibits glucoseinduced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulinreceptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. This mechanism may account for the induction of central insulin resistance by free fatty acids.
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