Sirt3基因在调节胰岛素抵抗小鼠卵母细胞线粒体功能和氧化应激损伤中的作用及其机制研究

The incidence of obesity overlapped with hyperinsulinism and insulin resistance is increasing, and this linked to infertility and poor reproductive outcome. Therefore, the relationship between the metabolic syndrome and reproductive dysfunction is an active area of study, which is increasingly puzzling the infertile female. Maternal hyperinsulinism and insulin resistance impaires oocyte quality and the embryo developmental potentiality, which is one of the main reasons for female infertility. The incidence of infertility with hyperinsulinism and insulin resistance but with normal serum glucose is common. So we established successfully the disease model with hyperinsulinism and insulin resistance but normal serum glucose. On the basis of this model, we will explore whether insulin resistance disrupts the mitochondrial function of mouse oocyte, cumulus and granulosa cells, and results in the oxidative stress. Furthermore, we will study how hyperinsulinism disrupts oocyte quality through affecting the insulin signals and how Sirt3 affects the insulin signals in oocyte and cumulus cell in insulin-resistant mouse. The research is expected to provide basis and targets for preventing and treating the infertile female with insulin resistance.

高胰岛素血症和胰岛素抵抗是导致女性生育力下降的重要致病因素之一。卵子质量下降所导致的胚胎发育潜能的改变是其主要原因，进一步探讨其发病机制对临床治疗该疾病具有重要的意义。本项目通过在前期已建好的模拟临床不孕症中高发病率的高胰岛素血症和胰岛素抵抗但血糖正常的小鼠疾病模型的基础上探讨：1）高胰岛素血症对小鼠卵母细胞、卵丘和颗粒细胞线粒体功能和氧化应激的损伤；2）高胰岛素血症对卵母细胞和卵丘细胞的胰岛素信号通路影响和调节；3）Sirt3是否通过影响胰岛素信号通路参与对卵母细胞质量的损伤。研究成果将为临床防治高胰岛素血症和胰岛素抵抗并不孕的妇女提供理论依据和治疗靶点。

高胰岛素血症和胰岛素抵抗是导致女性生育力下降的重要致病因素之一。卵子质量下降所导致的胚胎发育潜能的改变是其主要原因，进一步探讨其发病机制对临床治疗该疾病具有重要的意义。本项目通过给小鼠喂养高脂饮食模拟临床不孕症中高发病率的高胰岛素血症和胰岛素抵抗但血糖正常的小鼠疾病模型的基础上探讨：1）高胰岛素血症对小鼠卵母细胞、卵丘和颗粒细胞线粒体功能和氧化应激的损伤；2）高胰岛素血症对卵母细胞和卵丘细胞的胰岛素信号通路影响和调节；3）Sirt3是否通过影响胰岛素信号通路参与对卵母细胞质量的损伤。本项目中，申请者综合运用多种研究手段，获得较好的研究结果。研究取得结果如下：1）胰岛素抵抗和高胰岛素血症导致了卵母细胞、颗粒细胞和卵丘细胞的线粒体功能障碍和氧化应激损伤，其氧化应激损伤进一步影响卵母细胞质量，导致小鼠卵母细胞受精能力下降，胚胎质量差，生育能力下降；2）胰岛素抵抗和高胰岛素血症导致小鼠卵巢组织尤其卵丘细胞的Sirt3-JNK-IRS1信号通路发生改变，Sirt3等蛋白表达下降，并激活p-JNK，减少IRS表达，导致卵母细胞易受氧化应激损伤, 这可能是胰岛素抵抗小鼠生育力下降的可能机制之一。研究成果将为临床防治高胰岛素血症和胰岛素抵抗并不孕的妇女提供理论依据和治疗靶点，对生殖医学临床实践具有重要指导意义。