Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Cell. 2010 Feb 5;140(3):338-48. doi: 10.1016/j.cell.2010.01.001.
As chronic inflammation is a hallmark of obesity, pathways that integrate nutrient- and pathogen sensing pathways are of great interest in understanding the mechanisms of insulin resistance, type 2 diabetes, and other chronic metabolic pathologies. Here, we provide evidence that double-stranded RNA-dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. Dietary and genetic obesity features marked activation of PKR in adipose and liver tissues and absence of PKR alleviates metabolic deterioration due to nutrient or energy excess in mice. These findings demonstrate PKR as a critical component of an inflammatory complex that responds to nutrients and organelle dysfunction.
由于慢性炎症是肥胖的一个标志，因此在理解胰岛素抵抗、2 型糖尿病和其他慢性代谢性疾病的机制中，整合营养和病原体感应途径的途径引起了极大的关注。在这里，我们提供的证据表明，双链 RNA 依赖性蛋白激酶（PKR）可以对营养信号以及内质网（ER）应激做出反应，并协调其他关键炎症激酶（如 c-Jun N-末端激酶（JNK））的活性，以调节胰岛素的作用和代谢。PKR 还可以直接靶向和修饰胰岛素受体底物，从而将营养物质和胰岛素作用与特定的病原体反应系统整合在一起。饮食和遗传肥胖的特点是脂肪组织和肝脏组织中 PKR 的明显激活，而 PKR 的缺失可减轻因营养或能量过剩而导致的代谢恶化。这些发现表明 PKR 是对营养和细胞器功能障碍做出反应的炎症复合物的关键组成部分。
