Decreased neurotensin induces ovulatory dysfunction via the NTSR1/ERK/EGR1 axis in polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the predominant cause of subfertility in reproductive-aged women; however, its pathophysiology remains unknown. Neurotensin (NTS) is a member of the gut–brain peptide family and is involved in ovulation; its relationship with PCOS is unclear. Here, we found that NTS expression in ovarian granulosa cells and follicular fluids was markedly decreased in patients with PCOS. In the in vitro culture of cumulus–oocyte complexes, the neurotensin receptor 1 (NTSR1) antagonist SR48692 blocked cumulus expansion and oocyte meiotic maturation by inhibiting metabolic cooperation and damaging the mitochondrial structure in oocytes and surrounding cumulus cells. Furthermore, the ERK1/2-early growth response 1 pathway was found to be a key downstream mediator of NTS/NTSR1 in the ovulatory process. Animal studies showed that in vivo injection of SR48692 in mice reduced ovulation efficiency and contributed to irregular estrus cycles and polycystic ovary morphology. By contrast, NTS partially ameliorated the ovarian abnormalities in mice with dehydroepiandrosterone-induced PCOS. Our findings highlighted the critical role of NTS reduction and consequent abnormal NTSR1 signaling in the ovulatory dysfunction of PCOS, suggesting a potential strategy for PCOS treatment.

Keywords

neurotensin / neurotensin receptor 1 / early growth response 1 / polycystic ovary syndrome / ovulatory disfunction

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Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (Nos. 2022YFC2703204 and 2021YFC2701104), the National Natural Science Foundation of China (Nos. 81971343 and 82171623), the National Institutes of Health Project (No. 1R01HD085527), the Innovative research team of high-level local universities in Shanghai (No. SHSMU-ZLCX20210200), Shanghai Commission of Science and Technology (Nos. 21XD1401900 and 20DZ2270900), Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (No. GWVI-11.1-36) and Shanghai’s Top Priority Research Center Construction Project (No. 2023ZZ02002).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1089-z and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Dongshuang Wang, Meiling Zhang, Wang-Sheng Wang, Weiwei Chu, Junyu Zhai, Yun Sun, Zi-Jiang Chen and Yanzhi Du declare that they have no competing interests.

The study was approved by the Ethics Committee of Ren Ji hospital, Shanghai Jiao Tong University School of Medicine and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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