Meal Initiation and Energy Homeostasis: Role of Ghrelin

进餐开始和能量稳态：生长素释放肽的作用

• 批准号: 6623176
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 23.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623176
• 关键词: anorexia; appetite; appetite regulatory center; behavior test; bioenergetics; biological signal transduction; blood tests; body weight; clinical research; fasting; hormone inhibitor; hormone regulation /control mechanism; human subject; hunger; laboratory rat; leptin; neuroendocrine system; nonhuman therapy evaluation; nutrient intake activity; nutrition disorder chemotherapy; obesity; overeating; phenotype; plasma; somatotropin; weight loss

DESCRIPTION (Provided by applicant): Obesity is a leading cause of morbidity and mortality worldwide, and wasting is a dread complication of common diseases such as cancer. As there are no highly effective medical treatments for either condition, elucidating the mechanisms that govern food intake and body weight is a high priority. Major insights have been gained regarding the processes that govern long-term energy homeostasis, as well as those that signal post-prandial satiety and terminate individual meals. In contrast, the factor(s) that mediate the powerful sensation of pre-prandial hunger and initiate meals remain largely unknown. The novel hormone ghrelin is a reasonable candidate for a physiological meal initiator. It is secreted by the stomach, circulates in blood, and powerfully and rapidly increases food intake in rodents. We have shown that plasma levels dramatically rise and fall shortly before and after every meal in humans. Other observations suggest that ghrelin may also participate in long-term energy homeostasis. Chronic administration increases body weight, blockade of basal levels decreases food intake, and ghrelin levels increase with acute or chronic energy deficit, consistent with an adaptive response. We propose to address the following questions. (1) Is ghrelin a physiological meal initiator? We will determine if plasma ghrelin surges predict voluntarily initiated meals in humans isolated from external meal cues. In rats we will evaluate whether physiological doses of ghrelin initiate meals, and if chronic blockade of endogenous ghrelin signaling disrupts meal initiation. (2) Does ghrelin regulate long-term energy homeostasis? In order to assess whether ghrelin participates in the adaptive response to an energy deficit, we will evaluate the effect of both fasting and diet-induced weight loss on human plasma ghrelin levels. In rats we will determine if a ghrelin antagonist blunts the adaptive hyperphagic and hypothalamic neuroendocrine responses to fasting, ameliorates the obesity phenotype of leptin deficiency, or causes weight loss in normal animals. 3) What regulates ghrelin expression? Extending our finding of meal-related ghrelin suppression in humans, we will determine in humans and rats the relative contributions to circulating ghrelin levels of enteral vs. parenteral nutrients, gastric distension, specific classes of macronutrients, leptin, fasting, and other meal-regulated gut peptides. 4) Is ghrelin effective as a drug to treat cancer anorexia in a rat model?

描述（由申请人提供）：肥胖是发病的主要原因 消瘦是常见疾病的可怕并发症 例如癌症。由于没有高效的医学治疗方法， 条件，阐明控制食物摄入和体重的机制 是最重要的对这些过程有了重要的认识 控制着长期能量平衡， 餐后饱腹感并终止单独进餐。而反观 调节餐前饥饿强烈感觉的因素， 初始膳食仍然很大程度上未知。新的激素ghrelin是一种 作为生理膳食引发剂的合理候选物。它是由 胃，在血液中循环，并有力地和迅速地增加食物摄入量 在啮齿类动物中。我们已经证明，血浆水平会在短时间内急剧上升和下降 在人类的每顿饭之前和之后其他观察表明，胃饥饿素 也可能参与长期的能量平衡。长期给药 增加体重，阻断基础水平降低摄食量， 生长激素释放肽水平随着急性或慢性能量缺乏而增加，与 适应性反应。我们建议处理以下问题。(1)是 胃饥饿素是一种生理性进食引发剂？我们将确定血浆胃促生长素 激增预测自愿发起的膳食在人类隔离从外部 用餐提示。在大鼠中，我们将评估生理剂量的生长激素释放肽是否 开始进食，如果内源性生长激素释放肽信号传导的慢性阻断 干扰进食开始。(2)生长激素释放肽调节长期能量吗 体内平衡？为了评估ghrelin是否参与了适应性 针对能量不足，我们将评估禁食和 饮食诱导的体重减轻对人血浆胃饥饿素水平的影响。在大鼠中， 确定胃饥饿素拮抗剂是否钝化适应性贪食， 下丘脑神经内分泌反应禁食，改善肥胖 瘦素缺乏症的表型，或在正常动物中引起体重减轻。第三章 什么调节ghrelin的表达？扩大了我们对与饮食有关的 我们将在人类和大鼠中确定 肠内与肠外对循环胃饥饿素水平的相对贡献 营养素，胃扩张，特定种类的大量营养素，瘦素， 禁食和其他膳食调节的肠道肽。4)生长激素释放肽作为一种 在大鼠模型中治疗癌症厌食症的药物？