Solinas Giovanni, Naugler Willscott, Galimi Francesco, Lee Myung-Shik, Karin Michael
Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive, MC 0723, La Jolla, CA 92093-0723, USA.
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16454-9. doi: 10.1073/pnas.0607626103. Epub 2006 Oct 18.
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 beta-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.
JNKs是治疗肥胖症和2型糖尿病的理想靶点。在小鼠肥胖的饮食和遗传模型中，观察到JNK活性持续增加，而JNK缺陷可预防肥胖诱导的胰岛素抵抗。用JNK抑制剂治疗肥胖小鼠也有类似的胰岛素增敏作用。我们现在证明，用饱和脂肪酸棕榈酸处理可导致原代小鼠肝细胞和胰腺β细胞中JNK持续激活和胰岛素抵抗。在胰腺β细胞中，棕榈酸处理部分通过干扰胰岛素受体底物1和2在干扰与活化胰岛素受体结合的位点的磷酸化，从而干扰自分泌胰岛素信号传导，抑制葡萄糖诱导的胰岛素基因转录。这种机制可能解释了游离脂肪酸诱导中枢胰岛素抵抗的原因。
