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

Abstract

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 Kiss1ARHneurons, controlling GnRH pulses, and the sexually dimorphic Kiss1AVPV/PeNneurons controlling the preovulatory LH surge driving ovulation. In the present study, we show thatMc4ris expressed within Kiss1ARHand Kiss1AVPV/PeNneurons.In vivo, deletion of MC4R from Kiss1 neurons in female mice replicates the reproductive impairments of MC4RKO mice without inducing obesity. Conversely, reinsertion of MC4R in Kiss1 neurons of MC4R null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype.In vitro, we show that MC4R activation excites Kiss1ARHneurons through direct synaptic actions. In contrast, Kiss1AVPV/PeNneurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1AVPV/PeNneurons to induce the preovulatory LH surge driving ovulation in females. Our findings demonstrate that POMCARHneurons acting through MC4R, directly regulate reproductive function in females by stimulating the “pulse generator” activity of Kiss1ARHneurons and restricting the activation of Kiss1AVPV/PeNneurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of metabolic regulation of fertility.SignificanceWomen with inactivating mutations in proopiomelanocortin (POMC) or melanocortin receptor 4 (MC4R) genes are severely obese and display various degrees of reproductive disorders; however, the mechanisms by which MC4R regulates reproduction remain unknown. Here, we show that the melanocortins, known for their fundamental role in the control of energy balance, also play a direct role in reproduction by modulating the tonic and surge-like release of GnRH/LH via direct actions on MC4R of Kiss1 neurons. These findings identify a direct link between the neural regulation of metabolism and fertility and offer a new platform for the development of novel approaches to treat reproductive deficiencies derived from metabolic impairments.