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: 6463784
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 24.82万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6463784
• 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（申请人提供）：肥胖是发病率的主要原因 和全球死亡率，浪费是普通疾病的可怕并发症 例如癌症。由于没有任何高效的医疗治疗 条件，阐明控制食物摄入和体重的机制 是高度优先事项。关于过程已经获得了主要见解 控制长期能量稳态，以及那些发出信号的能量 餐后饱腹感并终止单个餐点。相反， 介导祖先饥饿感的强大感觉和的因素 启动餐仍然在很大程度上未知。新颖的激素生长素是 合理的生理餐起始候选人。它是由 胃，血液循环，有力而快速增加食物摄入量 在啮齿动物中。我们已经表明，血浆水平急剧上升和下降很快 每顿饭之前和之后人类。其他观察结果表明ghrelin 也可能参与长期能量稳态。长期给药 增加体重，封锁基础水平会降低食物的摄入量，并 刺激素水平随着急性或慢性能量不足而增加，与 自适应反应。我们建议解决以下问题。 （1）是 ghrelin是生理餐的引发剂？我们将确定是否血浆生长素素 潮流预测，从外部孤立的人类中自愿发起的餐 进餐线索。在大鼠中，我们将评估生理剂量的生长素 启动饭菜，以及内源性生长素蛋白信号传导的慢性封锁 破坏饭菜的启动。 （2）生长素素会调节长期能量 稳态？为了评估生长素是否参与自适应 对能源不足的响应，我们将评估禁食的效果和 饮食诱导的人血浆血浆水平的体重减轻。在老鼠中，我们会 确定生长素蛋白拮抗剂是否会钝化自适应倍感和 下丘脑神经内分泌对禁食的反应，改善肥胖症 瘦素缺乏的表型，或导致正常动物的体重减轻。 3） 是什么调节生长素素的表达？扩展我们与进餐有关的发现 在人类中，我们将在人类和大鼠中确定 对肠内循环的肠道循环肽水平与肠胃外的相对贡献 养分，胃扩张，特定类别的大量营养素，瘦素， 禁食和其他饮食调节的肠肽。 4）生长素有效作为一个 在大鼠模型中治疗癌症厌食症的药物？