Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance
Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance
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DOI：
10.1073/pnas.0603509103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Hotamisligil, Gokhan S.
中科院分区：
文献类型：
--
作者：
Tuncman, Gurol;Hirosumi, Jiro;Hotamisligil, Gokhan S.
在培养的细胞和整个动物中，c-jun氨基末端激酶(JNKs)是炎症和干扰胰岛素作用的关键调节因子。肥胖会增加总的JNK活性，而JNK1而不是JNK2的缺乏会导致肥胖减少和胰岛素敏感性提高。有趣的是，在JNK2(-/-)小鼠中观察到了高于正常水平的JNK激活，特别是在肝脏中，这表明在分离的突变小鼠中，可能掩盖了JNK2代谢活性的亚型之间存在相互作用。为了探讨JNK2亚型在代谢稳态中的作用，我们将JNK1(-/-)和JNK2(-/-)小鼠杂交，并检测了所产生的突变等位基因组合中的体重和葡萄糖代谢。在所有被检测的存活基因中，我们只观察到JNK1(-/-)和JNK1(+/-)JNK2(-/-)小鼠体重减轻和胰岛素敏感性增加。这两组小鼠的总JNK活性和肝组织中细胞因子的表达也比所有其他被检测的基因类型都要低。这些数据表明，JNK2亚型也参与了代谢调节，但当JNK1完全表达时，由于两种亚型之间的调控串扰，其功能并不明显。
The c-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action in cultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiency results in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2(-/-) mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1(-/-) and Jnk2(-/-) mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. Among all of the viable genotypes examined, we observed only reduced body weight and increased insulin sensitivity in Jnk1(-/-) and Jnk1(+/-)Jnk2(-/-) mice. These two groups of mice also exhibited reduced total JNK activity and cytokine expression in liver tissue compared with all other genotypes examined. These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms.