The role of follicular fluid glutamine in granulosa cell apoptosis and ovulation

The study found that FSH controls follicular fluid (FF) glutamine levels to determine ovulation. In mice, 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.

Key findings from the study include:

1. Patients with polycystic ovary syndrome (PCOS) have elevated glutamine levels in their follicular fluid compared to non-PCOS individuals.
2. Follicle Stimulating Hormone (FSH) plays a pivotal role in directing glutamine synthesis, which is essential for follicle development and the regulation of ovulation. FSH promotes the synthesis of glutamine in granulosa cells, leading to increased glutamine levels in the follicular fluid.
3. As FSH levels decrease, the supply of glutamine in the follicular fluid diminishes, resulting in the apoptosis of granulosa cells. This process contributes to the breakdown of the follicle wall from the inside out, which is a crucial step in ovulation.
4. Manipulating glutamine levels and/or the apoptotic pathways in granulosa cells could serve as a novel and effective intervention strategy for PCOS. By adjusting these factors, it may be possible to alleviate PCOS symptoms and improve ovulation outcomes.

The study reveals that FSH controls FF glutamine levels, which in turn regulate GC apoptosis via the ASK1-JNK pathway. Dysregulated glutamine levels contribute to the development of PCOS traits. Therapeutic interventions targeting the glutamine synthesis pathway and ASK1-JNK signaling hold potential for treating PCOS and restoring normal ovulatory function. The work entitled " Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation " was published on Protein & Cell (published on Jan. 3, 2024).