Meal Initiation and Energy Homeostasis: Role of Ghrelin

描述(申请人提供)：肥胖是导致发病的主要原因 和世界范围内的死亡率，而消瘦是常见疾病的可怕并发症 比如癌症。因为对于这两种疾病都没有非常有效的治疗方法 条件，阐明控制食物摄入量和体重的机制 是一个高度优先的问题。已经获得了关于这些过程的主要见解 管理长期能量动态平衡的，以及那些发出信号的 餐后饱腹感和终止个别用餐。相比之下， 调节餐前饥饿和强烈感觉的因素(S) 主动进餐在很大程度上仍不为人所知。新的激素Ghrelin是一种 生理餐发起人的合理人选。它是由 胃，在血液中循环，并有力地和迅速地增加食物的摄入量 在啮齿动物身上。我们已经证明，血浆水平很快就会急剧上升和下降 在人类的每顿饭前后。其他观察结果表明，Ghrelin 也可能参与长期的能量动态平衡。慢性给药 增加体重，阻断基础水平减少食物摄入量，以及 Ghrelin水平随着急性或慢性能量缺乏而增加，这与 一种适应性反应。我们建议解决以下问题。(1)是 Ghrelin是一种生理性膳食启动剂吗？我们将确定血浆生长激素释放素 病毒激增预测与外界隔离的人类自愿开始进餐 餐桌提示。在大鼠身上，我们将评估生理剂量的Ghrelin 开始进餐，如果慢性阻断内源性Ghrelin信号 打乱了进餐的开始。(2)Ghrelin是否调节长期能量 动态平衡？为了评估Ghrelin是否参与适应性 为了应对能源短缺，我们将评估禁食和 饮食诱导的体重减轻对人体血浆生长激素水平的影响。在老鼠身上，我们会 确定Ghrelin拮抗剂是否钝化适应性高吸血症和 下丘脑神经内分泌对禁食的反应，改善肥胖 瘦素缺乏的表型，或导致正常动物体重减轻。3) 是什么调节了Ghrelin的表达？扩大我们对与膳食相关的研究的发现 在人类中抑制生长激素释放素，我们将在人类和大鼠身上确定 肠内与肠外给药对循环Ghrelin水平的相对贡献 营养素，胃胀，特定种类的常量营养素，瘦素， 禁食，以及其他饮食调节的肠肽。4)Ghrelin作为一种 治疗大鼠癌症厌食症的药物？

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?