Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation

Kai-Hui Zhang; Fei-Fei Zhang; Zhi-Ling Zhang; Ke-Fei Fang; Wen-Xing Sun; Na Kong; Min Wu; Hai-Ou Liu; Yan Liu; Zhi Li; Qing-Qing Cai; Yang Wang; Quan-Wei Wei; Peng-Cheng Lin; Yan Lin; Wei Xu; Cong-Jian Xu; Yi-Yuan Yuan; Shi-Min Zhao

doi:10.1093/procel/pwad065

Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation

Protein Cell. 2024 Jan 3:pwad065. doi: 10.1093/procel/pwad065. Online ahead of print.

Authors

Kai-Hui Zhang^{1

2

3}, Fei-Fei Zhang¹, Zhi-Ling Zhang^{1

2

4}, Ke-Fei Fang¹, Wen-Xing Sun⁵, Na Kong⁶, Min Wu⁶, Hai-Ou Liu¹, Yan Liu¹, Zhi Li¹, Qing-Qing Cai¹, Yang Wang¹, Quan-Wei Wei⁷, Peng-Cheng Lin⁸, Yan Lin^{1

2}, Wei Xu^{1

2

9}, Cong-Jian Xu¹, Yi-Yuan Yuan^{1

2}, Shi-Min Zhao^{1

2

4

8}

Affiliations

¹ The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China.
² Shanghai Key Laboratory of Metabolic Remodeling, and Children's Hospital of Fudan University, Shanghai 200032, China.
³ Pediatric Research Institute, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan 250022, China.
⁴ School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 2000438, China.
⁵ Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226019, China.
⁶ Reproductive Medicine Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
⁷ Department of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210014, China.
⁸ Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining 810007, China.
⁹ The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.

PMID: 38167949
DOI: 10.1093/procel/pwad065

Abstract

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH and ASK1-JNK pathway are targetable to alleviate PCOS.

Keywords: FSH; PCOS; glutamine; granulosa cells; ovulation.