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

为了保证生殖过程中有足够的能量，能量平衡的激素和神经信号影响着生殖的中枢生理。因此，无论是正向还是负向能量稳态的不适应变化都会对生殖成功和生育力产生巨大影响。尽管代谢状态与生殖之间的生理相互作用具有重要意义，但代谢与生殖之间的潜在机制和神经通路尚不完全清楚。黑素皮质素中枢系统已被证明参与生殖和代谢的整合。先前的研究已经确定α-促黑素细胞激素（α-MSH）、针刺相关蛋白（AgRP）和黑素皮质素4受体（MC4R）调节生殖功能的多个方面。在本文中，我们提供的数据表明，黑素皮质素-3受体（MC3R）在能量和生殖状态的整合中起着关键的双向作用。我们进一步发现MC3R KO小鼠的下丘脑-垂体-性腺轴存在缺陷。因此，该项目的长期目标是进一步了解MC3R在健康和疾病表型中介导生殖功能的作用。在第一个目标中，我将研究生殖生理学，并利用转基因工具和药理学来测试MC3R通过调节AgRP末端gaba能的释放来调节LH脉搏。第二个目的是研究MC3R调节LH脉搏的潜在机制。本研究将使用内镜成像技术来验证MC3R通过增加弓状kisspeptin神经元AgRP末端gaba能释放来降低LH脉性的假设。总之，这些研究将进一步深入了解黑素皮质素系统，特别是MC3R，在调节HPG轴中的作用，并可能为未来治疗生殖疾病（包括多囊卵巢综合征）的治疗干预提供新的靶点。

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.