Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates

G Solinas, W Naugler, F Galimi… - Proceedings of the …, 2006 - National Acad Sciences
G Solinas, W Naugler, F Galimi, MS Lee, M Karin
Proceedings of the National Academy of Sciences, 2006National Acad Sciences
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 …
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 glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor 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.
National Acad Sciences