Role of the Melanocortin-3 Receptor in Regulation of the HPG Axis

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To assure adequate energy resources for the energetically demanding process of reproduction, central reproductive physiology is influenced by hormonal and neural signals of energy balance. As a result, maladaptive changes in energy homeostasis in either the positive or negative direction can exert dramatic effects on reproductive success and fertility. Despite the importance of physiological interactions between metabolic state and reproduction, the underlying mechanisms and neural pathways linking metabolism and reproduction are not fully understood. The central melanocortin system has been demonstrated to be involved in the integration of reproduction and metabolism. Previous studies have determined that alpha melanocyte stimulating hormone (α-MSH), agouti related protein (AgRP), and melanocortin 4 receptor (MC4R) modulate multiple aspects of reproductive function. In this proposal, we provide data demonstrating that the melanocortin-3 receptor (MC3R) plays critical, bidirectional roles in integration of energy and reproductive states. We further show defects in the hypothalamic-pituitary-gonadal axis in MC3R KO mice. Therefore, the long-term goal of this project is to further understand the role of MC3R in mediating reproductive function in both healthy and disease phenotypes. In the first aim, I will examine reproductive physiology and utilize transgenic tools and pharmacology to test that the MC3R modulates LH pulsatility by regulating GABAergic release in AgRP terminal sites. The second aim will examine a potential mechanism by which MC3R might regulate LH pulsatility. This aim will use endomicroscopic imaging to test the hypothesis that the MC3R can reduce LH pulsatility by increasing GABAergic release in AgRP terminal sites on arcuate kisspeptin neurons. Together, these studies will provide further insight into the role of the melanocortin system, in particular MC3R, in regulating the HPG axis and may reveal new targets for future therapeutic intervention for treatment of reproductive disorders, including PCOS.