线粒体来源多肽MOTS-c 在延长由饮食诱导的肥胖及胰岛素抵抗小鼠卵巢寿命中的作用及其机制研究

Obesity and insulin resistance is one of the important pathogenic factors resulting in a decline of female fertility. The incidence of infertility with obesity and insulin resistance but with normal serum glucose is common. Reduced ovarian reserve may be one of the main reasons for female infertility, which seriously affects the women's reproductive health and reproductive life. To further understand the pathogenesis has important clinical significance for the prevention and treatment of this disease. On the basis of our previously finishedthe National Natural Science Foundation Youth Program about insulin resistance disruption of the mitochondrial function resulting in oxidative stress. we successfully established the mouse disease model with hyperinsulinism and insulin resistance but normal serum glucose. Furthermore, we also found some new clues about the occurrence of this disease in a long term scientific research and clinical work. In this study, we will explore whether obesity and insulin resistance disrupts the function of oocyte and results in primordial follicle depletion. Secondly, we will study whether the mitochondrial-derived peptide MOTS-c regulates the primordial follicular activation and depletion through MOTS-c-LKB1-AMPK-mTOR path and subsequently causes premature ovarian failure. Thirdly, we will explore whether MOTS-c can be used to improve poor oocyte quality and decreased ovarian function caused by obesity and insulin resistance. The research is expected to provide new treatment for the growing number of older and obese patients with metabolic syndrome and decreased ovarian reserve, and thus extend the reproductive life of the female.

肥胖及胰岛素抵抗是导致女性生育力下降的重要致病因素，而卵巢储备功能的下降可能是其重要的根源之一，严重影响了女性生殖健康和生殖寿命。本项目在已完成的关于胰岛素抵抗对卵母细胞线粒体功能和氧化应激损伤的青年科学基金的基础上，利用前期已建好的模拟临床不孕症中肥胖和胰岛素抵抗小鼠疾病模型，并基于临床工作中新发现的重要线索，深入研究：1）肥胖和胰岛素抵抗是否损害了卵巢功能，加速了始基卵泡的消耗；2）线粒体来源的多肽MOTS-c是否通过激活MOTS-c-LKB1-AMPK-mTOR信号通路调控对卵巢始基卵泡的启动募集和消耗速率，加速卵巢功能的衰退；3）MOTS-c是否可以治疗和改善肥胖和胰岛素抵抗所致卵子质量和卵巢功能减退。研究成果不仅具有理论意义，也将可能为临床日益增多的肥胖及其高龄合并代谢综合征及卵巢储备功能减退的患者提供新的治疗手段，为改善和延长女性生殖寿命提供科学证据和方法。

肥胖及胰岛素抵抗是导致女性生育力下降的重要致病因素，而卵巢储备功能的下降是其重要的根源之一，严重影响了女性生殖健康和生殖寿命。本项目在已完成的关于胰岛素抵抗对卵母细胞线粒体功能和氧化应激损伤的青年科学基金的基础上，利用前期已建好的模拟临床不孕症中肥胖和胰岛素抵抗小鼠疾病模型，并基于临床工作中新发现的重要线索，深入研究了：1）肥胖和胰岛素抵抗是否加速了始基卵泡的消耗，从而损害卵巢功能；2）线粒体来源的多肽MOTS-c是否通过激活MOTS-c-LKB1-AMPK-mTOR信号通路调控对卵巢始基卵泡的启动募集和消耗速率，影响卵巢功能的衰退；3）MOTS-c是否可以治疗和改善肥胖和胰岛素抵抗所致卵子质量和卵巢功能减退。本项目综合运用多种研究手段，获得较好的研究结果。得到的主要结论如下：1）肥胖和胰岛素抵抗导致卵巢中卵泡数减少，严重损害卵巢功能；2）肥胖小鼠卵母细胞通过 MOTS-c -LKB1-AMPK-mTOR 信号通路影响卵巢功能和卵子质量；3）MOTS-c不仅可以改善肥胖和胰岛素抵抗导致卵巢功能减退，适量的MOTS-c还可以延缓老龄导致的卵巢衰竭；4）线粒体来源的多肽MOTS-c可能通过影响受体PEX5与影响与PTS1蛋白结合从而影响SKL基质蛋白进入过氧化物酶体，受损的过氧化物酶体功能通过影响超长链脂肪酸和长链脂肪酸的代谢进而影响小鼠的早期胚胎发育。研究成果不仅具有理论意义，也将可能为临床日益增多的肥胖及其高龄合并代谢综合征及卵巢储备功能减退的患者提供新的潜在治疗手段，为改善和延长女性生殖寿命提供科学证据和方法。