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

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 MC4RKO 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^ARHneurons, controlling GnRH pulses, and the sexually dimorphic Kiss1^AVPV/PeNneurons controlling the preovulatory LH surge. Here, we show thatMc4rexpressed in Kiss1 neurons is required for fertility in females.In vivo, deletion ofMc4rfrom Kiss1 neurons in female mice replicates the reproductive impairments of MC4RKO mice without inducing obesity. Conversely, reinsertion ofMc4rin 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^ARHvs Kiss1^AVPV/PeNneurons and show that MC4R activation excites Kiss1^ARHneurons through direct synaptic actions. In contrast, Kiss1^AVPV/PeNneurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1^AVPV/PeNneurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMC^ARHneurons acting through MC4R, directly regulate reproductive function in females by stimulating the “pulse generator” activity of Kiss1^ARHneurons and restricting the activation of Kiss1^AVPV/PeNneurons 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.