Talbi Rajae, Stincic Todd L, Ferrari Kaitlin, Ji Hae Choi, Walec Karol, Medve Elizabeth, Gerutshang Achi, Leon Silvia, McCarthy Elizabeth A, Rønnekleiv Oline K, Kelly Martin J, Navarro Victor M
Harvard Medical School, Boston, United States.
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, United States.
Elife. 2025 Jul 17;13:RP100722. doi: 10.7554/eLife.100722.
Inactivating mutations in the melanocortin 4 receptor () 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 neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1 neurons controlling the preovulatory luteinizing hormone (LH) surge. Here, we show that expressed in Kiss1 neurons regulates fertility in females. In vivo, deletion of from Kiss1 neurons in female mice replicates the reproductive impairments of Mc4r KO mice without inducing obesity. Conversely, re-insertion of 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 versus Kiss1 neurons and show that Mc4r activation excites Kiss1 neurons through direct synaptic actions. In contrast, Kiss1 neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1 neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMC neurons acting through MC4R directly regulate reproductive function in females by stimulating the 'pulse generator' activity of Kiss1 neurons and restricting the activation of Kiss1 neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of the metabolic regulation of fertility by the melanocortin system.
黑皮质素4受体（MC4R）基因的失活突变会导致单基因肥胖。有趣的是，女性患者还表现出不同程度的生殖障碍，这与MC4R基因敲除（KO）雌性小鼠的生育力低下表型一致。然而，MC4R调节生殖的细胞机制尚不清楚。Kiss1神经元通过两个不同的群体直接刺激促性腺激素释放激素（GnRH）的释放：控制GnRH脉冲的Kiss1神经元，以及控制排卵前促黄体生成素（LH）激增的性二态性Kiss1神经元。在这里，我们表明在Kiss1神经元中表达的MC4R调节雌性动物的生育力。在体内，雌性小鼠Kiss1神经元中MC4R的缺失复制了MC4R KO小鼠的生殖障碍，而不会诱发肥胖。相反，在MC4R基因缺失小鼠的Kiss1神经元中重新插入MC4R可恢复发情周期和LH脉冲性，而不会减轻其肥胖表型。在体外，我们剖析了MC4R对Kiss1与Kiss1神经元的具体作用，并表明MC4R激活通过直接突触作用兴奋Kiss1神经元。相比之下，Kiss1神经元通常受到MC4R激活的抑制，除非在雌二醇水平升高的情况下，从而促进Kiss1神经元的激活，以诱导驱动雌性排卵的LH激增。我们的研究结果表明，通过MC4R起作用的阿黑皮素原（POMC）神经元通过刺激Kiss1神经元的“脉冲发生器”活性并将Kiss1神经元的激活限制在雌二醇依赖性LH激增的时间，直接调节雌性动物的生殖功能，从而揭示了黑皮质素系统对生育力进行代谢调节的新途径。
