Nesfatin-1对多囊卵巢综合征高雄激素血症及胰岛素抵抗的调节作用及其机制

Insulin resistance (IR) and hyperandrogenism are the core of polycystic ovary syndrome (PCOS). The role of metabolic surgery in weight loss, improvement of metabolic and fertility disorders begins to appear, and the research of targets can be avoided the risk of surgery and the expansion of clinical applications. Blood Nesfatin-1 was reduced during PCOS. Applicants learned that Nesfatin-1 was significantly elevated after metabolic surgery and that peripheral Nesfatin-1 improved PCOS’s IR and hyperandrogenism in mice. Nesfatin-1 could active AMPK to improve glucose and lipid metabolism and the activation of AMPK can inhibit the proliferation of theca cells and the secretion of androgen. It is speculated that Nesfatin-1 may improve the insulin sensitivity of the target organs and inhibit the secretion of androgens by the activation of AMPK to improve PCOS. Therefore, it is proposed that exogenous Nesfatin-1 be administered to PCOS mice. With the help of in vivo and in vitro culture methods, it is clear that Nesfatin-1 can improve the function of PCOS caused by metabolic disorders. To explore the mechanism involved in AMPK/mTOR signaling pathway, and single cell sequencing was used to preliminarily identify the transcriptome differential gene expression of membrane cells under the action of Nesfatin-1. We hope to provide a new theoretical basis and scientific basis for clinical prevention and treatment of PCOS.

胰岛素抵抗(IR)及高雄激素血症是引发多囊卵巢综合征(PCOS)的核心，代谢手术在减重、改善代谢及生育力障碍中的作用初显，寻找其作用靶点可规避手术风险并扩大临床应用。PCOS时血Nesfatin-1(NES-1)减少，申请者读博士期间发现代谢手术后胃激素NES-1明显升高，上调外周NES-1可改善小鼠PCOS的IR和高雄激素血症。结合NES-1通过激活AMPK参与改善糖脂代谢及激活AMPK下调mTOR可抑制卵泡膜细胞增殖和雄激素分泌，故推测NES-1可能通过激活AMPK改善机体靶器官胰岛素敏感性、抑制卵巢雄激素分泌而改善PCOS。本项目拟对PCOS小鼠外源给予NES-1，借助在体及离体培养手段，明确NES-1改善代谢紊乱所致PCOS的作用，探讨AMPK/mTOR信号通路参与的机制，并采用单细胞测序来初步明确NES-1作用下的膜细胞转录组差异基因表达。希冀为临床防治PCOS提供新的科学依据。

多囊卵巢综合征( polycystic ovary syndrome，PCOS) 是一种以胰岛素抵抗、雄激素增高和卵巢多囊为主要临床特征的内分泌疾病，也是育龄女性最常见的生殖内分泌紊乱性疾病之一，可导致女性不孕，严重危害女性健康。PCOS 的病因尚不明确，其核心病理机制是胰岛素抵抗和高雄激素血症，因此，PCOS治疗的重点在于降低体重、改善胰岛素抵抗及高雄激素血症，恢复卵巢功能。本项目通过高脂喂养及灌胃给来曲唑的方式建立小鼠PCOS模型，在此模型基础上通过外源性给予Nesfatin-1增加小鼠外周血Nesfatin-1，对Nesfatin-1在体内发挥作用进行的研究并探讨其机制；通过卵巢细胞原代培养，研究Nesfatin-1在体外实验中的作用及机制，并从基因表达角度来寻找Nesfatin-1作用靶点及机制，进一步解释Nesfatin-1改善PCOS胰岛素抵抗及高雄激素血症的作用机制。通过本课题研究，我们发现并验证了Nesfatin-1是代谢手术改善PCOS胰岛素抵抗及高雄激素血症潜在的重要靶点的科学假设。并且通过分子生物学研究，明确Nesfatin-1能够激活AMPK信号通路，调控糖代谢，改善胰岛素抵抗，同时具有激活卵巢膜细胞AMPK，抑制mTOR信号通路，从而抑制雄激素分泌的作用机制，为探索新的改善PCOS胰岛素抵抗和高雄激素血症的治疗方法提供科学依据。进一步利用单细胞测序，精准检测Nesfatin-1作用于卵巢膜细胞的基因靶点，为下一步深入探究Nesfatin-1的作用机制，在转录组水平精准定位Nesfatin-1借助于何种调控途径影响代谢及雄激素合成打基础。本课题研究结果也为临床治疗PCOS提供了理论依据和新的思路。