Ghrelin Regulation: Implications for Understanding Obesity

描述（由申请人提供）：Ghrelin是一种肠源性酰化肽激素，刺激生长激素和ACTH的分泌，以及促氧生成。我们的中心论点是饥饿素通过以下方式保护哺乳动物免受饥饿：增加食欲和食物摄入量；增加生长激素分泌以保护瘦体重；减少运动活动以保存卡路里；调节分配，包括葡萄糖稳态。该应用的总体假设是：(1)皮质醇和胰岛素是正常日常喂养和禁食模式中ghrelin释放的主要负调节因子，(2)这种特定的控制机制被肥胖改变，因此缺乏足够的ghrelin抑制会导致暴饮暴食。我们的实验室已经开发了灵敏和特异性的三明治检测完整的活性乙酰胃饥饿素和去乙酰胃饥饿素。使用这些试验，我们将解决以下具体目标：1：确定搏动性酰基和去酰基胃饥饿素分泌与胰岛素、皮质醇和生长激素血浆浓度之间的时间关系。这将为预测具体目标2和3中直接干预的结果提供初步数据。此外，这些数据还可以直接比较苗条和肥胖之间的关系。这些假设将使用ghrelin释放的最小数学模型进行测试（Specific Aim 4）。2：确定皮质醇对ghrelin分泌的影响，以确定其在ghrelin分泌的日变化中的作用。这些实验的结果将把饥饿素由皮质醇调节的假设转化为一个最小的数学模型。3：判断胰岛素是否抑制胃饥饿素分泌，葡萄糖相关胃饥饿素抑制是否由胰岛素介导。有人提出，胰岛素对胃饥饿素的抑制将取决于胰岛素敏感性/抵抗，类似于使用血糖胰岛素钳测量的葡萄糖处理方式。这些实验的结果将有助于将胰岛素调节胃饥饿素的假设转化为最小的数学模型。4：通过ghrelin调节最小模型（MMGR）确定瘦体和肥胖者ghrelin调节的差异，并确定肥胖中ghrelin调节异常的机制。为了统一特定目标2和3中胃饥饿素、胰岛素和皮质醇之间的关系，我们将重建系统相互作用，验证皮质醇和胰岛素是胃饥饿素分泌的主要控制因素这一生理假设的一致性，并确定调节胃饥饿素分泌的整体在肥胖中发生改变的方式。我们的研究有望阐明胃饥饿素参与肥胖发展的潜在机制；这可能会导致治疗肥胖和相关疾病的新方法，如糖尿病和代谢综合征。项目描述：我们的研究有望阐明胃饥饿素在肥胖发展中的潜在机制；这可能会导致治疗肥胖和相关疾病的新方法，如糖尿病和代谢综合征。

DESCRIPTION (provided by applicant): Ghrelin is a gut-derived acylated peptide hormone that stimulates secretion of growth hormone and ACTH, as well as orexigenesis. Our central thesis is that ghrelin protects mammals against starvation by: increasing appetite and food intake; increasing secretion of GH to protect lean body mass; decreasing locomotor activity to preserve calories; and regulating partitioning, including glucose homeostasis. The overall hypothesis of this application is that (1) cortisol and insulin are the dominant negative regulators of ghrelin release during normal daily patterns of feeding and fasting, and (2) this specific control mechanism is altered by obesity, such that the lack of adequate ghrelin suppression contributes to overeating. Our laboratory has developed sensitive and specific sandwich assays for intact active acyl-ghrelin and des-acyl ghrelin. Using these assays, we will address the following specific aims: 1: Determine the temporal relationships between pulsatile acyl- and des-acyl ghrelin secretion and plasma concentrations of insulin, cortisol and growth hormone in healthy lean and obese adults. This will provide the preliminary data for predicting the outcomes of the direct interventions in Specific Aims 2 and 3. In addition, the data will allow for the direct comparison of the same relationships in lean versus obese. The hypotheses will be tested using a minimal mathematical model of ghrelin release (Specific Aim 4). 2: Determine the effect of cortisol on ghrelin secretion to determine its role in diurnal variation in ghrelin secretion. The results of these experiments will translate the hypothesis of ghrelin regulation by cortisol into a minimal mathematical model. 3: Determine whether insulin inhibits ghrelin secretion and whether glucose-related ghrelin suppression is mediated by insulin. It is proposed that suppression of ghrelin by insulin will depend on insulin sensitivity/resistance in a similar fashion to glucose disposal as measured using a euglycemic insulin clamp. The results of these experiments will assist the translation of the hypothesis of ghrelin regulation by insulin into a minimal mathematical model. 4: Identify differences in ghrelin regulation between lean and obese subjects and determine the mechanism(s) for dysregulation of ghrelin in obesity using a minimal model of ghrelin regulation (MMGR). To unify the relationships between ghrelin, insulin and cortisol from Specific Aims 2 and 3, we will reconstruct the system interactions and verify the consistency of the physiological hypotheses that cortisol and insulin comprise the dominant controls of the secretion of ghrelin and determine the manner in which the ensemble that regulates the secretion of ghrelin is altered in obesity. Our studies are expected to illuminate underlying mechanisms involving ghrelin in the development of obesity; this may lead to new approaches to the treatment for obesity and related conditions, such as diabetes mellitus and Metabolic Syndrome.PROJECT NARRATIVE: Our studies are expected to illuminate underlying mechanisms involving ghrelin in the development of obesity; this may lead to new approaches to the treatment for obesity and related conditions, such as diabetes mellitus and Metabolic Syndrome.