Ghrelin Regulation: Implications for Understanding Obesity

描述(申请人提供)：Ghrelin是一种来自肠道的酰化多肽激素，可刺激生长激素和ACTH的分泌，以及食欲。我们的中心论点是，Ghrelin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GH的分泌以保护瘦体重；减少运动活动以保存卡路里；以及调节分配，包括葡萄糖动态平衡。这一应用的总体假设是：(1)在正常的日常进食和禁食模式中，皮质醇和胰岛素是生长激素释放的主要负调节因素，(2)肥胖改变了这一特定的控制机制，因此缺乏足够的生长激素抑制导致暴饮暴食。我们的实验室已经建立了灵敏和特异的完整活性酰基Ghrelin和去酰基Ghrelin的夹心检测方法。使用这些检测方法，我们将解决以下具体目标：1：确定健康、瘦和肥胖成年人的脉动性酰基和去酰基生长激素分泌与血浆胰岛素、皮质醇和生长激素浓度之间的时间关系。这将为预测具体目标2和3的直接干预结果提供初步数据。此外，这些数据将允许直接比较瘦和肥胖的相同关系。这些假设将使用Ghrelin释放的最小数学模型(特定目标4)进行验证。2：测定皮质醇对Ghrelin分泌的影响，以确定其在Ghrelin分泌昼夜变化中的作用。这些实验的结果将把皮质醇调节Ghrelin的假设转化为一个最小的数学模型。3：确定胰岛素是否抑制Ghrelin的分泌，以及葡萄糖相关的Ghrelin抑制是否由胰岛素介导。有人提出，胰岛素对Ghrelin的抑制将取决于胰岛素的敏感性/抵抗，其方式类似于使用正常血糖的胰岛素钳夹测量葡萄糖处理的方式。这些实验的结果将有助于将胰岛素调节Ghrelin的假说转化为最小数学模型。4：确定瘦身和肥胖受试者胃促生长素调节的差异，并使用胃促生长素调节的最小模型(MMGR)确定肥胖症中胃促生长素调节失调的机制(S)。为了统一来自特定目标2和3的Ghrelin、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构成Ghrelin分泌的主要控制的生理学假设的一致性，并确定调节Ghrelin分泌的整体在肥胖中发生变化的方式。我们的研究有望阐明Ghrelin在肥胖症发展中的潜在机制；这可能导致治疗肥胖症和相关疾病的新方法，如糖尿病和代谢综合征。PROJECT简介：我们的研究有望阐明Ghrelin在肥胖症发展中的潜在机制；这可能导致治疗肥胖症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.