NEK7通过激活炎性小体导致机体胰岛素抵抗的机制研究

Obesity induced chronic inflammation is the main cause of type 2 diabetes and insulin resistance. High fat diet not only leads to obesity, but also systemic chronic inflammation. Thus, insulin resistance is mainly caused by the lipotoxicity. However, the detailed mechanisms by which the adipocytes secret cytokines responding to lipotoxicity are still elusive. NLRP3 inflammasome is recently thought to be an important reason for the cytokine secreted by cells responding to extracellular stimuli. It is reported that NEK7 exerts a crucial role in the activation of inflammasome in macrophages responding to ER stress and ROS generation. Our observation revealed that NEK7 was highly expressed in the adipose tissues of db/db mice and high fat diet induced diabetic mice. Knockdown of NEK7 in insulin resistance adipocytes increased cellular glucose uptake. Furthermore, we verified that NEK7 could interact with NLRP3 in HEK293 cells. Based on these results, we hypothesize that NEK7 can interact with NLRP3 responding to the lipotoxicity induced ER stress and ROS generation. The NEK7-NLRP3 complex can thus activate cellular inflammasome and lead to systemic insulin resistance. We will comprehensively boost our study on the role of NEK7 leading to the activation of inflammasone and systemic insulin resistance in vitro and in vivo.

高脂含量的饮食引起的慢性炎症是导致机体胰岛素抵抗的重要原因。然而，脂肪细胞应答高脂刺激产生慢性炎症的机制并不清楚。NLRP3炎性小体近年来被发现是细胞应答外界刺激产生炎症因子的重要机制。NEK7是重要的NLRP3结合蛋白，在巨噬细胞中可以应答细胞内质网应激和ROS的增加激活炎性小体，从而促进炎性因子大量分泌。我们的前期工作表明，NEK7在2型糖尿病db/db模型小鼠和高脂诱导小鼠的脂肪组织中高表达，并且NEK7可以调控胰岛素抵抗的脂肪细胞对葡萄糖的吸收能力，我们还发现，NEK7的确可以和NLRP3蛋白发生相互作用。因此，我们提出假设，高脂条件下，脂肪细胞应答游离脂肪酸刺激发生内质网应激和细胞内ROS增加，促进NEK7与NLRP3发生相互结合并激活炎性小体，促进机体胰岛素抵抗的发生。本课题将从细胞水平和整体动物水平，全面，系统地研究NEK7及其激活的炎性小体在机体胰岛素抵抗发生过程中的作用。

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