Hirosumi Jiro, Tuncman Gürol, Chang Lufen, Görgün Cem Z, Uysal K Teoman, Maeda Kazuhisa, Karin Michael, Hotamisligil Gökhan S
Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.
Nature. 2002 Nov 21;420(6913):333-6. doi: 10.1038/nature01137.
Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.
肥胖与胰岛素抵抗密切相关，是2型糖尿病的主要危险因素，然而这种关联的分子机制尚不清楚。c-Jun氨基末端激酶（JNKs）可在培养细胞中干扰胰岛素作用，并被炎性细胞因子和游离脂肪酸激活，这些分子与2型糖尿病的发生有关。我们在此表明，肥胖时JNK活性异常升高。此外，在两种不同的小鼠肥胖模型中，JNK1缺失导致肥胖减轻、胰岛素敏感性显著改善以及胰岛素受体信号传导能力增强。因此，JNK是肥胖和胰岛素抵抗的关键介质，也是治疗的潜在靶点。
