Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis.
Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis.
复制标题
二甲双胍通过抑制卵巢铁下垂改善小鼠多囊卵巢综合征
DOI：
10.3389/fendo.2023.1070264
复制
发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
多囊卵巢综合征（PCOS）是育龄妇女常见的代谢紊乱性疾病，其发病机制十分复杂。铁凋亡在多囊卵巢综合征中的作用是一个新的发现，其机制尚不清楚。二甲双胍是治疗PCOS的常用药物，但二甲双胍是否能改善PCOS患者卵泡发育和卵巢功能的研究较少。本研究旨在利用PCOS小鼠模型，从卵巢功能的角度研究二甲双胍对PCOS的影响，并探讨二甲双胍对PCOS小鼠铁凋亡通路的干预作用。采用4-5周龄C57 BL/6 J雌性小鼠，以来曲唑（1 mg/kg/d）结合高脂饲料灌胃21 d建立PCOS模型，并设对照组。造模后随机分为PCOS模型组和二甲双胍治疗组（Met组），每组6只，Met组给予二甲双胍200 mg/kg/d灌胃，连续28 d。监测体重、发情周期、糖耐量试验（OGTT）和胰岛素抵抗试验（ITT）。处死小鼠，收集血清和卵巢。ELISA法检测血清相关激素（E2、LH、FSH、TP）的变化。用于分子生物学实验的卵巢，以通过蛋白质印迹和qPCR检测GPX 4、SIRT 3、AMPK/p-AMPK和mTOR/p-mTOR的变化。与模型组相比，Met组小鼠体重明显减轻，动情周期恢复。OGTT和ITT结果显示糖耐量和胰岛素抵抗改善。形态学结果显示，二甲双胍治疗后，卵巢多囊病变减少，卵巢功能恢复，SIRT 3和GPX 4表达升高。WB结果显示，模型组大鼠卵巢组织p-mTOR和p-AMPK表达明显降低，MET组大鼠卵巢组织p-mTOR和p-AMPK表达逆转。本研究证实二甲双胍不仅能改善PCOS小鼠的体重和代谢紊乱，还能改善卵巢功能障碍，并探讨二甲双胍可能通过SIRT 3/AMPK/mTOR通路调节铁凋亡来改善PCOS。我们的研究补充了二甲双胍改善PCOS的机制。
PCOS is a common metabolic disorder in women of reproductive age, which pathogenesis is very complex. The role of ferroptosis in PCOS is a novel finding, and the mechanistic studies are not clear. Metformin is a commonly used drug of PCOS but few studies on whether metformin can improve the follicle development and ovarian function in PCOS. We aims to use PCOS mouse model to study the effect of metformin on PCOS based on the ovarian function and explored the regulation of metformin in PCOS mice by intervening in ferroptosis pathway. C57 BL/6J female mice aged 4-5 weeks were purchased and gavaged with letrozole (1 mg/kg/day) combined with high-fat diet for 21days to establish PCOS model, and control group was set up. After modeling, the mice were divided into PCOS model group and metformin treatment group (Met) (n=6).The Met group were gavaged metformin (200 mg/kg/day) for 28 days. The body weight, estrous cycle, glucose tolerance test (OGTT)and insulin resistance test (ITT) were monitored. Then, The mice were euthanized to collect serum and ovaries. Elisa was used to detect changes in related serum hormones (E2, LH, FSH, TP). Ovaries used for molecular biology experiments to detect changes in GPX4, SIRT3, AMPK/p-AMPK, and mTOR/p-mTOR by Western blot and qPCR. Compared with the model group mice, body weight was significantly reduced, and their estrous cycle was restored in Met group. The results of OGTT and ITT showed an improvment of glucose tolerance and insulin resistance. Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. WB results demonstrated that the expressions of p-mTOR and p-AMPK in ovaries were significantly reduced in Model group, but reversed in MET group. Our study confirmed metformin could not only improve body weight and metabolism disorders, but also improve ovarian dysfunction in PCOS mice.In addition, we explored metformin could regulate ferroptosis to improve PCOS via the SIRT3/AMPK/mTOR pathway. Our study complements the mechanisms by which metformin improves PCOS.
登录
查看更多内容
DOI：
10.1056/nejmcp1514916
发表时间：
2016-07-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
McCartney CR;Marshall JC
通讯作者：
Marshall JC
影响因子：
2.6
作者：
Xu Y;Wu Y;Huang Q
通讯作者：
Huang Q
影响因子：
2.6
作者：
Chen J;Qin C;Zhou Y;Chen Y;Mao M;Yang J
通讯作者：
Yang J
影响因子：
3.2
作者：
Pasquali R;Stener-Victorin E;Yildiz BO;Duleba AJ;Hoeger K;Mason H;Homburg R;Hickey T;Franks S;Tapanainen JS;Balen A;Abbott DH;Diamanti-Kandarakis E;Legro RS
通讯作者：
Legro RS
二甲双胍：对其潜在适应症的综述。
DOI：
10.2147/dddt.s141675
发表时间：
2017
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Wang YW;He SJ;Feng X;Cheng J;Luo YT;Tian L;Huang Q
通讯作者：
Huang Q