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 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 females by stimulating the 'pulse generator' activity of Kiss1(ARH) neurons and restricting the activation of Kiss1(AVPV/PeN) 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.