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 PCOS. However, the expression and role of the neurokinin B-neurokinin 3 receptor (NKB-NK3R) system in the local ovarian tissue of PCOS haven't 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. This article is protected by copyright. All rights reserved.