The Role of Estradiol and Sex in the Effects of Ghrelin on Meal Patterns and Fos-

描述(申请人提供)：性腺类固醇是影响哺乳动物摄食量和体重的众多因素之一。荷尔蒙对这些过程的影响在雌性大鼠中尤其显著，雌性大鼠在卵巢切除后显示出食物摄入量和体重的大幅增加(Wade，1975)。雌激素在控制人类食物摄入量和能量平衡方面的关键作用被绝经后肥胖率大大增加的事实所证明(美国妇产科医师学会，2005年)。雌二醇对调节饮食的神经系统的作用也可能在一定程度上解释了食物摄入量和饮食失调的性别差异，这在年轻女性中更常见(Sodersten&Bergh，2003)。虽然雌激素对食物摄入量的影响似乎部分是通过与参与控制食物大小的CCK系统的相互作用来调节的(Butera等人，1993；Geary等人，1995)，但观察到CCK拮抗剂并不能完全逆转雌二醇的厌食作用，这表明CCK不是调节雌激素引起的摄食减少的唯一因素(Eckel&Geary，1999)。按照这些思路，Ghrelin是一种主要在胃中合成的多肽荷尔蒙，它与大脑中的受体结合，并调节生长激素的分泌。对人类和啮齿动物的研究表明，Ghrelin水平在进餐前增加，并且Ghrelin治疗增加了雄性大鼠的食物摄入量(Beck等人，2002；Cummings&Schwartz，2003)。一些证据表明，生长激素的产生、分泌及其对行为和新陈代谢的影响受到雌激素的影响(Matsubara等人，2004年；Kemp等人，2005年)。这些数据表明，Ghrelin和雌二醇之间的相互作用可能是雌二醇抑制摄食行为以及去势和停用雌激素所导致的体重增加的基础。这一领域的前两个实验的总体目标是研究Ghrelin对雌性和雄性大鼠食物摄入量和进食模式的影响，并评估雌激素调节Ghrelin刺激食欲的能力。研究摄食行为的微结构变化将更好地理解雌二醇和Ghrelin与食物摄入量的神经生物学控制相互作用的方式(Smith，2000)。第三个实验将通过检测雌激素对雌性大鼠大脑中Ghrelin诱导的c-Fos表达的影响，来评估雌激素影响Ghrelin信号的中央处理的能力。从这些实验中获得的信息将有助于我们理解控制食物摄入量的机制，并为卵巢激素影响进食和促进食物摄入量性别差异的机制提供更多信息。雌激素与Ghrelin等促食欲信号相互作用的能力，也可能有助于揭示与更年期和肥胖相关的因素，以及饮食障碍中性别差异的潜在原因。-人类健康意义在这一修订的申请中，我讨论了拟议的研究对人类健康和疾病具有重要意义的方式，以及拟议的研究如何提高我们对雌激素在绝经后妇女体重增加和肥胖发展中的作用、食物摄入量性别差异背后的机制以及饮食失调的内分泌基础的理解，饮食失调的内分泌基础可能导致厌食症和神经性贪食症的患病率存在巨大的性别差异。

DESCRIPTION (provided by applicant): Gonadal steroids are among the numerous factors influencing food intake and body weight in mammals. Hormonal effects on these processes are particularly striking in female rats, which show large increases in food intake and body weight after ovariectomy (Wade, 1975). A key role of estrogen in the control of food intake and energy balance in humans is evidenced by the fact that the incidence of obesity increases greatly after menopause (American College of Obstetricians and Gynecologists, 2005). The actions of estradiol on neural systems that regulate eating may also account in part for sex differences in food intake and eating disorders, which occur much more frequently in young women (Sodersten & Bergh, 2003). Although the effects of estradiol on food intake appear to be mediated in part by interactions with CCK systems that participate in the control of meal size (Butera et al., 1993; Geary et al., 1995), the observation that CCK antagonists do not completely reverse the anorectic action of estradiol indicates that CCK is not the only factor involved mediating the reduction in feeding caused by estrogen (Eckel & Geary, 1999). Along these lines, ghrelin is a peptide hormone synthesized principally in the stomach that binds to a receptor in the brain and regulates growth hormone secretion. Studies in humans and rodents indicate that ghrelin levels increase prior to a meal and that ghrelin treatment increases food intake in male rats (Beck et al., 2002; Cummings & Schwartz, 2003). Several lines of evidence indicate that ghrelin production, secretion, and its effects on behavior and metabolism are influenced by estrogen (Matsubara et al., 2004; Kemp et al., 2005). These data suggest that interactions between ghrelin and estradiol may underlie the inhibitory effects of estradiol on feeding behavior and the weight gain caused by ovariectomy and estrogen withdrawal. The general goals of the first two experiments in this AREA grant proposal are to examine the effects of ghrelin on food intake and meal patterns in female and male rats and evaluate the ability of estrogen to modulate the appetite-stimulating effects of ghrelin. Examining changes in the microstructure of ingestive behavior will provide a better understanding of the ways in which estradiol and ghrelin interact with neurobiological controls of food intake (Smith, 2000). The third experiment will evaluate the ability of estradiol to influence the central processing of the ghrelin signal by examining the effects of estradiol on ghrelin-induced c-Fos expression in the brains of female rats. Information obtained from these experiments will contribute to our understanding of mechanisms involved in the control of food intake and provide additional information on the mechanisms by which ovarian hormones affect eating and contribute to sex differences in food intake. The ability of estrogen to interact with orexigenic signals like ghrelin may also shed light on the factors associated with menopause and obesity as well as potential causes of sex differences in eating disorders. - Human Health Significance In this revised application I have discussed the ways in which the proposed research has significance for human health and disease and how the proposed studies can improve our understanding of the role of estrogen in the development of weight gain and obesity in postmenopausal women, mechanisms underlying sex differences in food intake, and the endocrine basis of eating disorders that can contribute to the large sex difference in the prevalence of anorexia and bulimia nervosa.