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

为了确保有足够的能量来满足生殖过程中的能量需求，中枢生殖生理受到荷尔蒙和神经能量平衡信号的影响。因此，能量平衡在正向或负向的不适应变化都会对生殖成功和生育产生巨大影响。尽管代谢状态和生殖之间的生理相互作用很重要，但连接代谢和生殖的潜在机制和神经通路尚不完全清楚。中枢黑素皮质素系统已被证明参与生殖和新陈代谢的整合。以前的研究已经确定，α-黑素细胞刺激素(α-MSH)、刺鼠相关蛋白(AgRP)和黑素皮质素4受体(MC4R)调节生殖功能的多个方面。在这项建议中，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发挥着关键的双向作用。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在调节健康和疾病表型的生殖功能中的作用。在第一个目的中，我将研究生殖生理，并利用转基因工具和药理学来测试MC3R通过调节AgRP末端位置的GABA能释放来调节黄体生成素的搏动性。第二个目标将研究MC3R可能调节黄体生成素搏动性的潜在机制。这一目标将利用内窥镜成像来检验MC3R可以通过增加弓状Kisspeptin神经元AgRP末端位置的GABA能释放来降低黄体生成素的搏动性的假说。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轴方面的作用，并可能揭示未来治疗生殖障碍的新靶点，包括多囊卵巢综合征。

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.