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

描述（由申请方提供）：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。激素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术后食物摄入量和体重大幅增加（Wade，1975）。雌激素在控制人类食物摄入和能量平衡中的关键作用由绝经后肥胖症的发生率大大增加的事实证明（美国妇产科学院，2005）。雌二醇对调节进食的神经系统的作用也可能部分解释了食物摄入和进食障碍的性别差异，这在年轻女性中更常见（Sodersten & Bergh，2003）。虽然雌二醇对食物摄入的影响似乎部分地通过与参与控制膳食量的CCK系统的相互作用来介导（Butera等人，1993; Geary等人，1995），CCK拮抗剂不能完全逆转雌二醇的厌食作用的观察表明CCK不是介导由雌激素引起的摄食减少的唯一因素（Eckel & Geary，1999）。沿着这些路线，生长激素释放肽是一种主要在胃中合成的肽激素，其与大脑中的受体结合并调节生长激素分泌。在人类和啮齿动物中的研究表明，饥饿素水平在餐前增加，并且饥饿素治疗增加雄性大鼠的食物摄入（Beck等人，2002; Cummings & Schwartz，2003）。几条证据表明，生长激素释放肽的产生、分泌及其对行为和代谢的影响受到雌激素的影响（Matsubara等人，2004;肯普等人，2005年）的报告。这些数据表明，生长激素释放肽和雌二醇之间的相互作用可能是雌二醇对卵巢切除术和雌激素戒断引起的摄食行为和体重增加的抑制作用的基础。在这个区域拨款提案的前两个实验的总体目标是检查饥饿激素对雌性和雄性大鼠的食物摄入量和膳食模式的影响，并评估雌激素调节饥饿激素的食欲刺激作用的能力。检查摄食行为的微观结构变化将有助于更好地理解雌二醇和生长激素释放肽与食物摄入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查雌二醇对雌性大鼠脑中生长素释放肽诱导的c-Fos表达的影响来评价雌二醇影响生长素释放肽信号的中枢处理的能力。从这些实验中获得的信息将有助于我们了解参与控制食物摄入的机制，并提供更多的信息，卵巢激素影响进食的机制，并有助于食物摄入的性别差异。雌激素与促食欲信号（如ghrelin）相互作用的能力也可能揭示与更年期和肥胖相关的因素，以及饮食失调性别差异的潜在原因。- 人类健康的意义在这个修订后的申请中，我讨论了拟议的研究对人类健康和疾病具有意义的方式，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的理解，食物摄入性别差异的潜在机制，以及饮食失调的内分泌基础，这可能导致厌食症和神经性贪食症患病率的巨大性别差异。

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.