Hyperhomocysteinemia Promotes Insulin Resistance and Adipose Tissue Inflammation in PCOS Mice Through Modulating M2 Macrophage Polarization via Estrogen Suppression.
It has been shown that serum homocysteine (Hcy) levels are higher in women with polycystic ovary syndrome (PCOS). However, the specific role of hyperhomocysteinemia (HHcy) in the development of PCOS has never been reported. Adipose tissue inflammation is featured by the infiltration of macrophages, which plays a critical role in the pathogenesis of glucose and insulin intolerance. In this study, C57BL/6 mice were treated with dehydroepiandrosterone (DHEA) and/or a high methionine diet to induce PCOS and HHcy mice models. We showed that DHEA induced a PCOS-like phenotypes, irregular estrous cycles, weight gain, abnormal sex hormone production, glucose and insulin resistance, and polycystic ovaries. HHcy further intensified the effects DHEA on the metabolic, endocrinal, hormonal, and morphological changes in PCOS-like mice. In addition, HHcy attenuated the DHEA-induced increase in serum estrogen levels in mice. Furthermore, HHcy may exacerbate the insulin resistance in PCOS-like mice, most likely through modulating the macrophage M1/M2 polarization pathways via the suppression of estrogen. Most important, our clinical data showed that there were increases in serum Hcy levels in patients with PCOS. These findings deepen our understanding of the pathological roles of HHcy in the development of PCOS and provide a promising target for PCOS therapy in clinical application.
Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.|Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.|Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China.
Xinyu
X
Qi
Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.|Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.|Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China.
Bochun
B
Zhang
Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.|Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.|Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China.
Yue
Y
Zhao
Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.|Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.|Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China.
Rong
R
Li
Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.|Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.
Hsun-Ming
HM
Chang
Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.|Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.|Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China.
Yanli
Y
Pang
Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.|Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.|Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China.
Jie
J
Qiao
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D004967:Estrogens / Q000097:blood / Q000378:metabolism*; D005260:Female; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015434:Panniculitis / Q000209:etiology* / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000150:complications* / Q000276:immunology / Q000378:metabolism
D004967:Estrogens