Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the direct effects of PGRN <i>in vivo</i> and the underlying mechanisms between PGRN and impaired insulin sensitivity are not fully understood. In this study, mice treated with PGRN for 21 d exhibited the impaired glucose tolerance and insulin sensitivity, remarkable ER stress as well as attenuated insulin signaling in liver and adipose tissue but not in skeletal muscle. Furthermore, treatment of mice with phenyl butyric acid (PBA), a chemical chaperone alleviating ER stress, resulted in a significant restoration of systemic insulin sensitivity and recovery of insulin signaling induced by PGRN. Consistent with these findings <i>in vivo</i>, we also observed that PGRN treatment induced ER stress, impaired insulin signaling in cultured hepatocytes and adipocytes, with such effects being partially nullified by blockade of PERK. Whereas PGRN-deficient hepatocytes and adipocytes were more refractory to palmitate-induced insulin resistance, indicating the causative role of the PERK-eIF2α axis of the ER stress response in action of PGRN. Collectively, our findings supported the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing ER stress via the PERK-eIF2α dependent pathway.

颗粒蛋白前体（Progranulin, PGRN）近来被证实为糖代谢与胰岛素敏感性的重要调控因子。然而，PGRN在体内（in vivo）的直接作用，以及其与胰岛素敏感性受损之间的潜在机制，尚未完全阐明。本研究中，经PGRN处理21天的小鼠表现出糖耐量与胰岛素敏感性受损，肝脏及脂肪组织中出现显著的内质网应激（ER stress）与胰岛素信号通路减弱，而骨骼肌中未观察到此类变化。进一步研究发现，使用可缓解内质网应激的化学分子伴侣苯基丁酸（Phenyl butyric acid, PBA）处理小鼠，可显著恢复全身胰岛素敏感性，并逆转PGRN诱导的胰岛素信号通路损伤。与体内实验结果一致，体外实验中我们观察到，PGRN处理可诱导培养的肝细胞与脂肪细胞产生内质网应激、损伤胰岛素信号通路，而阻断蛋白激酶R样内质网激酶（PERK）可部分抵消这些效应。相较之下，PGRN缺陷型肝细胞与脂肪细胞对棕榈酸诱导的胰岛素抵抗抗性更强，这表明内质网应激应答的PERK-eIF2α通路在PGRN的生物学作用中发挥了关键介导功能。综上，本研究结果支持“PGRN是胰岛素抵抗的关键调控因子”这一观点，且PGRN至少可部分通过PERK-eIF2α依赖的通路诱导内质网应激，从而介导其生物学效应。