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

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.