Discovery of microglia gonadotropin‑releasing hormone receptor and its potential role in polycystic ovarian syndrome

Wang,Fan; Zhang,Zhenghong; Han,Junyong; Zheng,Jianjun; Wang,Xin; Wang,Zhengchao

doi:10.3892/mmr.2023.12964

Discovery of microglia gonadotropin‑releasing hormone receptor and its potential role in polycystic ovarian syndrome

Authors:
- Fan Wang
- Zhenghong Zhang
- Junyong Han
- Jianjun Zheng
- Xin Wang
- Zhengchao Wang
View Affiliations

Affiliations: Provincial University Key Laboratory of Sport and Health Science, School of Physical Education and Sport Sciences, Fujian Normal University, Fuzhou, Fujian 350007, P.R. China, Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350007, P.R. China, Fujian Key Laboratory of Medical Measurement, Fujian Academy of Medical Sciences, Fuzhou, Fujian 350001, P.R. China, Department of Obstetrics and Gynecology, Fujian Provincial Hospital, Shengli Clinical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
Published online on: February 16, 2023 https://doi.org/10.3892/mmr.2023.12964
Article Number: 77
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hypothalamic inflammation is a pathophysiological basis of polycystic ovarian syndrome (PCOS), while overactivated and/or excess M1 polarized microglia are considered to be the main reason for the occurrence of hypothalamic inflammation. Therefore, in vitro and in vivo experiments were performed to assess the relationships between microglia‑mediated inflammatory reactions and endocrine functions in the PCOS hypothalamus. The expression of gonadotropin‑releasing hormone (GnRH) receptor (GnRHR) was demonstrated in hypothalamic microglia, and it was found that low concentration, GnRH agonist, leuprolide acetate accelerated the expression of M2 polarization marker CD206, while high concentration leuprolide acetate increased the expression of M1 polarization marker CD86 in vitro. Furthermore, aerobic exercise not only reduced the levels of serum testosterone, luteinizing hormone and GnRH and the amount of overactivated microglia, but also increased the number of M2 microglia in the hypothalamus of letrozole‑induced PCOS rats. In combination, these results not only demonstrated the expression of GnRHR in hypothalamic microglia, but also demonstrated that GnRH can induce microglial polarization, while aerobic exercise may improve the microglia‑mediated inflammatory reaction by reducing the expression of GnRHR in the hypothalamic microglia of PCOS rats.

View Figures

View References

1	Wang F, Wang SB, Zhang ZH, Lin Q, Liu Y, Xiao Y, Xiao K and Wang ZC: Activation of NLRP3 inflammasome in the ovaries during the development and treatment of polycystic ovary syndrome. Int J Clin Exp Patho. 10:5022–5030. 2017.
2	da Costa CS, Oliveira TF, Freitas-Lima LC, Padilha AS, Krause M, Carneiro MTWD, Salgado BS and Graceli JB: Subacute cadmium exposure disrupts the hypothalamic-pituitary-gonadal axis, leading to polycystic ovarian syndrome and premature ovarian failure features in female rats. Environ Pollut. 269:1161542021. View Article : Google Scholar : PubMed/NCBI
3	Wang F, Zhang ZH, Xiao KZ and Wang ZC: Roles of hypothalamic-pituitary-adrenal axis and hypothalamus-pituitary-ovary axis in the abnormal endocrine functions in patients with polycystic ovary syndrome. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 39:699–704. 2017.PubMed/NCBI
4	Barlampa D, Bompoula MS, Bargiota A, Kalantaridou S, Mastorakos G and Valsamakis G: Hypothalamic inflammation as a potential pathophysiologic basis for the heterogeneity of clinical, hormonal, and metabolic presentation in PCOS. Nutrients. 13:5202021. View Article : Google Scholar : PubMed/NCBI
5	Lian Y, Zhao F and Wang W: Central leptin resistance and hypothalamic inflammation are involved in letrozole-induced polycystic ovary syndrome rats. Biochem Biophys Res Commun. 476:306–312. 2016. View Article : Google Scholar : PubMed/NCBI
6	Ávalos Y, Kerr B, Maliqueo M and Dorfman M: Cell and molecular mechanisms behind diet-induced hypothalamic inflammation and obesity. J Neuroendocrino. 30:e125982018. View Article : Google Scholar : PubMed/NCBI
7	André C, Guzman-Quevedo O, Rey C, Rémus-Borel J, Clark S, Castellanos-Jankiewicz A, Ladeveze E, Leste-Lasserre T, Nadjar A, Abrous DN, et al: Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation. Diabetes. 66:908–919. 2017. View Article : Google Scholar : PubMed/NCBI
8	Tang Y, Purkayastha S and Cai D: Hypothalamic microinflammation: A common basis of metabolic syndrome and aging. Trends Neurosci. 38:36–44. 2015. View Article : Google Scholar : PubMed/NCBI
9	Deczkowska A, Amit I and Schwartz M: Microglial immune checkpoint mechanisms. Nat Neurosci. 21:779–786. 2018. View Article : Google Scholar : PubMed/NCBI
10	Kite C, Lahart IM, Afzal I, Broom DR, Randeva H, Kyrou I and Brown JE: Exercise, or exercise and diet for the management of polycystic ovary syndrome: A systematic review and meta-analysis. Syst Rev. 8:512019. View Article : Google Scholar : PubMed/NCBI
11	Kim CH, Chon SJ and Lee SH: Effects of lifestyle modification in polycystic ovary syndrome compared to metformin only or metformin addition: A systematic review and meta-analysis. Sci Rep. 10:78022020. View Article : Google Scholar : PubMed/NCBI
12	Lim SS, Hutchison SK, Van Ryswyk E, Norman RJ, Teede HJ and Moran LJ: Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 3:CD0075062019.PubMed/NCBI
13	Park SY, Jeon YK and Choi J: Effects of calorie restriction and aerobic exercise on hypothalamic inflammation factors, appetite suppression neuropeptide and daily feed intake in obese mouse. Korean J Sports Sci. 26:935–945. 2017. View Article : Google Scholar
14	Dorfman MD, Krull JE, Douglass JD, Fasnacht R, Lara-Lince F, Meek TH, Shi X, Damian V, Nguyen HT, Matsen ME, et al: Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice. Nat Commun. 8:145562017. View Article : Google Scholar : PubMed/NCBI
15	Maslyukov PM, Emanuilov AI and Korzina MB: Development of neurotransmitter specificity in sympathetic ganglionic neurons. Auton Neurosci. 135:66–67. 2007. View Article : Google Scholar
16	Kafali H, Iriadam M, Ozardali I and Demir N: Letrozole-induced polycystic ovaries in the rat: A new model for cystic ovarian disease. Arch Med Res. 35:103–108. 2004. View Article : Google Scholar : PubMed/NCBI
17	Jie W, Xiang JY, Wang Y, Hui-Min L, Zhou S, Hou JP and Wang B: Effects of baicalin and geniposide on polarization of BV2 microglia. Chin J Pharmacol Toxicol. 33:911–912. 2019.
18	Brunk D: Moderate exercise helps insulin sensitivity in PCOS. Fam Prac. 35:22. 2005.
19	Cao SF, Hu WL, Wu MM and Jiang LY: Effects of exercise intervention on preventing letrozole-exposed rats from polycystic ovary syndrome. Reprod Sci. 24:456–462. 2017. View Article : Google Scholar : PubMed/NCBI
20	Nehir Aytan A, Bastu E, Demiral I, Bulut H, Dogan M and Buyru F: Relationship between hyperandrogenism, obesity, inflammation and polycystic ovary syndrome. Gynecol Endocrinol. 32:709–713. 2016. View Article : Google Scholar : PubMed/NCBI
21	Sati A, Prescott M, Holland S, Jasoni CL, Desroziers E and Campbell RE: Morphological evidence indicates a role for microglia in shaping the PCOS-like brain. J Neuroendocrinol. 33:e129992021. View Article : Google Scholar : PubMed/NCBI
22	Gao Y, Ottaway N, Schriever SC, Legutko B, García-Cáceres C, de la Fuente E, Mergen C, Bour S, Thaler JP, Seeley RJ, et al: Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia. 62:17–25. 2014. View Article : Google Scholar : PubMed/NCBI
23	Lee CH, Suk K, Yu R and Kim MS: Cellular contributors to hypothalamic inflammation in obesity. Mol Cells. 43:431–437. 2020.PubMed/NCBI
24	Zeng F, Wu Y, Li X, Ge X, Guo Q, Lou X, Cao Z, Hu B, Long NJ, Mao Y and Li C: Custom-made ceria nanoparticles show a neuroprotective effect by modulating phenotypic polarization of the microglia. Angew Chem Int Ed Eng. l57:5805–5812. 2018.
25	Zhao YN, Wang F, Fan YX, Ping GF, Yang JY and Wu CF: Activated microglia are implicated in cognitive deficits, neuronal death, and successful recovery following intermittent ethanol exposure. Behav Brain Res. 236:270–282. 2013. View Article : Google Scholar : PubMed/NCBI
26	Kawanishi N, Yano H, Yokogawa Y and Suzuki K: Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet induced obese mice. Exerc Immunol Rev. 16:105–118. 2010.PubMed/NCBI