POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons

作者：Rajae Talbi, Todd L. Stincic, Kaitlin Ferrari, Choi Ji Hae, Karol Walec, Elizabeth Medve, Achi Gerutshang, Silvia León, Elizabeth A. McCarthy, Oline K. Rønnekleiv, Martin J. Kelly, Víctor M. Navarro · 发表于：eLife · 年份：2025 · DOI：10.7554/elife.100722.4 · 被引用次数：6 · 研究领域：Hypothalamic control of reproductive hormones、Regulation of Appetite and Obesity、Ovarian function and disorders

Inactivating mutations in the melanocortin 4 receptor ( MC4R ) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of Mc4r KO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations: the Kiss1 ARH neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1 AVPV/PeN neurons controlling the preovulatory luteinizing hormone (LH) surge. Here, we show that Mc4r expressed in Kiss1 neurons regulates fertility in females. In vivo, deletion of Mc4r from Kiss1 neurons in female mice replicates the reproductive impairments of Mc4r KO mice without inducing obesity. Conversely, re-insertion of Mc4r in Kiss1 neurons of Mc4r null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we dissect the specific action of Mc4r on Kiss1 ARH versus Kiss1 AVPV/PeN neurons and show that Mc4r activation excites Kiss1 ARH neurons through direct synaptic actions. In contrast, Kiss1 AVPV/PeN neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1 AVPV/PeN neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMC ARH neurons acting through MC4R directly regulate reproductive function in fem...