Max Planck Institute for Neurological Research, Institute for Genetics, University of Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), Cologne, Germany.
PLoS One. 2013;8(1):e54247. doi: 10.1371/journal.pone.0054247. Epub 2013 Jan 17.
Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNK(C)). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNK(C) mice were crossed to Mck-Cre mice yielding JNK(SM-C) mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNK(SM-C) mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance.
肥胖症和相关代谢紊乱，如循环脂肪酸增加，导致肝脏、骨骼肌、脂肪组织甚至中枢神经系统中的炎症信号通路持续低度激活。炎症通路的激活反过来又会损害胰岛素信号，最终导致肥胖相关的 2 型糖尿病。传统的 JNK-1 敲除小鼠对高脂肪饮食诱导的胰岛素抵抗具有保护作用，这表明 JNK-1 抑制可能是改善肥胖患者葡萄糖代谢的一种潜在方法。然而，在肥胖过程中升高的 JNK-1 信号的细胞类型特异性作用尚未完全阐明。为了研究改变的 JNK-1 激活在骨骼肌中的功能贡献，我们生成了一种 ROSA26 插入小鼠品系，允许 Cre 可激活表达 JNK-1 组成型激活构建体（JNK(C)）。为了研究骨骼肌中 JNK-1 过度激活对胰岛素抵抗和葡萄糖代谢发展的影响，将 JNK(C)小鼠与 Mck-Cre 小鼠杂交，产生 JNK(SM-C)小鼠。然而，尽管肌肉特异性 JNK 激活增加，但与对照组相比，JNK(SM-C)小鼠的能量平衡和葡萄糖代谢基本没有改变。与这些发现一致，骨骼肌中 JNK-1 特异性缺失的肥胖小鼠不会影响能量和葡萄糖稳态。这些实验表明，骨骼肌中 JNK-1 的激活不能解释 JNK-1 介导的饮食诱导的胰岛素作用恶化的主要影响，并指出 JNK-1 在肥胖相关胰岛素抵抗发展过程中除了骨骼肌之外，在其他组织中的作用尚未得到充分认识。
