The overexpression of neurokinin B–neurokinin 3 receptor system exerts direct effects on the ovary under PCOS‐like conditions to interfere with mitochondrial function.

Problem: The increased hypothalamic neurokinin B (NKB) level may contribute to the hyperactive LH pulse secretion in Polycystic ovary syndrome (PCOS). However, the expression and role of the neurokinin B‐neurokinin 3 receptor (NKB‐NK3R) system in the local ovarian tissue of PCOS have not been clarified. We constructed in vivo and in vitro models to elucidate the mechanism of the NKB‐NK3R pathway in reproductive endocrine disorders of PCOS. Method of study: The granulosa cell line‐KGN cells were set in palmitic acid (PA) and dihydrotestosterone (DHT) to simulate the PCOS‐like conditions. And we used the high‐fat/high‐glucose diet to build a PCOS‐like mice model and neurokinin 3 receptor antagonist (NK3Ra) was administered to half of the mice. The expression of the NKB‐NK3R system, mitochondrial functions, hormone levels, and inflammatory state was evaluated. Results: The PCOS‐like stimulations induced the NKB‐NK3R system and MAPK‐ERK pathway overexpression in KGN cells, in an approximate dose and time‐dependent manner. The NKB‐NK3R system overactivated the MAPK‐ERK pathway to increase NNT overexpression, disturb NADH/NADPH pools, aggravate the oxidation state, and decrease ATP production. With overexpression of the NKB‐NK3R system in the local ovarian tissue, ovulatory dysfunction, progesterone deficiency, and pro‐inflammatory states were apparent in PCOS‐like mice. Antagonizing the receptor, NK3R, reversed the adverse reproductive endocrine phenotypes via improving mitochondrial dysfunction. Conclusions: In addition to the central regulation, local ovarian overexpression of the NKB‐NK3R system participated in the adverse reproductive endocrine phenotypes, supporting the therapeutic implications of NK3Ra for PCOS. [ABSTRACT FROM AUTHOR]