Metformin improves polycystic ovary syndrome and activates female germline stem cells in mice
- Author:
- No author available
- Journal Title:
- Acta Physiologica Sinica
- Issue:
- 3
- DOI:
- 10.13294/j.aps.2021.0090
- Key Word:
- 二甲双胍;多囊卵巢综合征;雌性生殖干细胞;AMPK/mTOR
Abstract： 多囊卵巢综合征(polycystic ovary syndrome,PCOS)是生育年龄妇女常见的一种复杂的内分泌及代谢异常所致的疾病,是女性不孕的重要因素.二甲双胍是临床应用最广泛的经典口服降糖药物,近年来被应用于PCOS治疗,但其作用机制尚不明确.本研究通过建立小鼠PCOS模型,论证二甲双胍对PCOS的改善作用及其机制.4～5周龄雌性C57BL/6J小鼠连续21天给予来曲唑(每天灌胃1 mg/kg)联合高脂饮食,建立PCOS模型.成模后灌胃给予二甲双胍(每天200 mg/kg),1个月后取材,期间检测体重并进行糖耐量试验.取材后行苏木素-伊红(H&E)染色检测卵巢病理改变;ELISA法测定血清中抗缪勒氏管激素(anti-Mullerian hormone,AMH)、卵泡刺激素(follicle-stimulating hormone,FSH)、黄体生成素(luteinizing hormone,LH)、雌二醇(E2)、睾酮等激素水平;免疫组织化学及免疫荧光染色法检测雌性生殖干细胞(female germline stem cells,FGSCs)标志物DDX4/MVH及PCNA表达及定位;Western blot检测小鼠卵巢中DDX4/MVH、PCNA、cyclin D2以及AMPK/mTOR通路蛋白.结果显示,PCOS小鼠在接受二甲双胍治疗后,体重逐渐恢复正常,糖耐量试验显示糖耐量明显改善,血清E2水平升高,AMH、LH、睾酮水平及LH/FSH比值下降,卵巢多囊病变减轻,闭锁卵泡减少,且具有增殖性的FGSCs数目明显增多,卵巢组织PCNA、cyclinD2等增殖相关蛋白增加,p-mTOR、p-AMPK等蛋白明显上调.以上结果提示,二甲双胍在改善PCOS高雄激素血症、糖耐量异常及卵巢多囊病变的同时,还可以促进FGSCs增殖并激活其功能,其作用可能与AMPK、mTOR磷酸化有关.这些发现为二甲双胍治疗PCOS以及改善卵泡发育提供了新的科学依据和方向.
- [1]张新颖,毛景东,杨晓燕,等.AMPK/mTOR信号通路的研究进展[J].2019,(3).
- [2]陈娇,张妍,钟媛媛.MicroRNA-141通过PI3K/Akt/mTOR信号通路促进PCOS卵巢颗粒细胞增殖的机制研究[J].2021,(7).
- [3]宋颖,李蓉.多囊卵巢综合征中国诊疗指南解读[J].2018,(10).
- [4]苗晋鑫,李秀敏,苗明三.多囊卵巢综合征动物模型数据挖掘及分析[J].2020,(2).
- [5]Zou, Kang,Wang, Jian,Bi, Haiwei,etc.Comparison of different in vitro differentiation conditions for murine female germline stem cells[J].2019,52(1).
- [6]Shrikhande Laxmi,Shrikhande Bhushan,Shrikhande Aditya.AMH and Its Clinical Implications[J].2020,70(5).
- [7]Yu,Jiang,Dantian,Zhu,Wenfeng,Liu,etc.Hedgehog pathway inhibition causes primary follicle atresia and decreases female germline stem cell proliferation capacity or stemness.[J].2019,10(1).
- [8]Xiaoyu Zhang,Yang Yang,Qin Xia,etc.Cadherin 22 participates in the self-renewal of mouse female germ line stem cells via interaction with JAK2 and β-catenin[J].2018,75(7).
- [9]Hoyos, Luis R.,Visser, Jenny A.,McLuskey, Anke,etc.Loss of anti-Mullerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classics polycystic ovary syndrome (PCOS)[J].2020,35(10).
- [10]White,Y.A.R.,Woods,D.C.,Takai,Y.,etc.Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women[J].2012,18(3).
- [11]Zou K,Yuan Z,Yang Z,etc.Production of offspring from a germline stem cell line derived from neonatal ovaries.[J].2009,11(5).
- [12]Xinbao, Ding,Guishu, Liu,Bo, Xu,etc.Human GV oocytes generated by mitotically active germ cells obtained from follicular aspirates.[J].2016.
- [13]Martin Michaud,Laurent Balardy,Guillaume Moulis,etc.Proinflammatory cytokines, aging, and age-related diseases.[J].2013,14(12).
- [14]Zhang Chao,Liu Xiao-Ran,Cao Yong-Chun,etc.Mammalian target of rapamycin\/eukaryotic initiation factor 4F pathway regulates follicle growth and development of theca cells in mice[J].2016.
- [15]Liu, Min,Zhu, Hongqiu,Zhu, Ying,etc.Guizhi Fuling Wan reduces autophagy of granulosa cell in rats with polycystic ovary syndrome via restoring the PI3K/AKT/mTOR signaling pathway[J].2021,270.
- [16]Garg, Deepika,Tal, Reshef.The role of AMH in the pathophysiology of polycystic ovarian syndrome[J].2016,33(1).
- [17]Sohrevardi, Seyed Mojtaba,Heydari, Behrooz,Azarpazhooh, Mahmoud Reza,etc.Therapeutic Effect of Curcumin in Women with Polycystic Ovary Syndrome Receiving Metformin: A Randomized Controlled Trial[J].2021,1308.
- [18]Renato Pasquali.Contemporary approaches to the management of polycystic ovary syndrome[J].2018,9(4).
- [19]Li, Shiqin,Wang, Meng,Chen, Yanghui,etc.Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells.[J].2017.
- [20]Zou K,Hou L,Sun K,etc.Improved efficiency of female germline stem cell purification using fragilis-based magnetic bead sorting.[J].2011,20(12).