Estradiol, MCH and Food Intake

描述(申请人提供)：尽管饮食失调在女性中比在男性中更普遍，但这种性别差异的机制尚不清楚。虽然环境和文化因素可能导致女性饮食失调的患病率更高，但越来越明显的是，生物因素也可能起到关键作用。近年来，卵巢激素雌二醇在包括人类在内的各种物种中发挥着强大的厌食作用，已成为普遍存在的进食障碍，特别是神经性厌食症的生物学危险因素。要了解雌二醇如何导致饮食失调，关键的第一步是确定它如何影响健康动物的正常食物摄入量控制。现有证据表明，雌二醇的厌食效应是通过与控制摄食行为的神经和内分泌系统的其他关键因素相互作用间接调节的。虽然众所周知，雌二醇会增加雌性大鼠对厌食性(抑制食欲)多肽和神经递质系统的敏感性，但我的初步数据表明，雌二醇也能够降低雌性大鼠对厌食性(食欲刺激)神经肽--黑色素浓缩激素(MCH)的敏感性。在目前的应用中，我建议研究雌激素减少MCH诱导的摄食能力的神经机制。我的工作假设是，雌二醇通过核雌激素受体(ER)减少MCH信号，从而减少食物摄入量。利用单标免疫组织化学方法，我将确定雌二醇是否会降低大脑中与食物摄入量控制有关的区域中MCH或MCH受体(MCHR1)的蛋白表达。我还将结合部位特定的雌三醇输注和脑室输注MCH，以确定大脑区域(S)，在那里雌二醇作用于减少MCH诱导的摄食。最后，我将研究ER是否在表达MCH和MCHR1的相同神经元中表达。这一系列研究有可能增加我们对雌二醇厌食作用机制的理解，这一知识可能最终揭示雌二醇是如何作为某些饮食相关疾病的风险因素发挥作用的。通过完成这项研究，我将学习新的技术，并进一步促进我的专业发展，使我能够达到成为一名独立科学家的最终目标。

DESCRIPTION (provided by applicant): Despite the fact that eating disorders are more prevalent in women than in men, the mechanism driving this sex difference is poorly understood. While environmental and cultural factors likely contribute to the greater prevalence of eating disorders in women, it is becoming increasing clear that biological factors may also play a key role. In recent years, the ovarian hormone estradiol, which exerts a potent anorexigenic effect in variety of species including humans, has emerged as a putative, biological risk factor for eating disorders in general, and anorexia nervosa in particular. A crucial first step in understanding how estradiol may contribute to eating disorders is to determine how it affects the normal controls of food intake in healthy animals. Available evidence suggests that the anorexigenic effect of estradiol is mediated indirectly through interactions with other key elements of the neural and endocrine systems controlling ingestive behavior. While it is well established that estradiol increases the female rat's sensitivity to anorexigenic (appetite suppressing) peptides and neurotransmitter systems, my preliminary data suggest that estradiol is also capable of decreasing the female rat's sensitivity to an orexigenic (appetite stimulating) neuropeptide, melanin-concentrating hormone (MCH). In the present application, I propose to examine the neural mechanisms underlying estradioPs ability to decrease MCH-induced feeding. My working hypothesis is that estradiol acts via nuclear estrogen receptors (ERs) to decrease MCH signaling and, as a consequence, decreases food intake. Using single-label immunohistochemistry, I will determine whether estradiol decreases MCH or MCH receptor (MCHR1) protein expression in brain regions implicated in the control of food intake. I will also combine site-specific infusions of estraidol with ventricular infusions of MCH in order to identify brain region(s) in which estradiol acts to decrease MCH-induced feeding. Finally, I will investigate whether ERs are expressed within the same neurons that express MCH and MCHR1. This series of studies has the potential to increase our understanding of the mechanism underlying estradiol's anorexigenic effect and this knowledge may ultimately reveal how estradiol functions as a risk factor for certain eating-related disorders. In completing this research, I will learn new techniques and further my professional development, allowing me to reach my ultimate goal of becoming an independent scientist.