Ghrelin Regulation: Implications for Understanding Obesity

生长素释放肽调节：对理解肥胖的影响

• 批准号: 7879064
• 负责人: MICHAEL O THORNER
• 金额: $ 1.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879064
• 关键词: Address; Adult; Biological Assay; Blood Glucose; Calories; Cells; Circadian Rhythms; Corticotropin; Data; Desire for food; Development; Diabetes Mellitus; Dominant-Negative Mutation; Dose; Eating; Fasting; Feeding Patterns; Glucose; Hormones; Hour; Hydrocortisone; Hyperphagia; Infusion procedures; Insulin; Insulin Resistance; Intervention; Laboratories; Lead; Mammals; Measures; Mediating; Metabolic; Metabolic syndrome; Modeling; Motor Activity; OGTT; Obesity; Oral; Outcome; Pattern; Physiological; Placebos; Plasma; Regulation; Relative (related person); Role; Serum; Somatotropin; Starvation; Stomach; System; Testing; Translating; Translations; Variant; Withdrawal; basal insulin; blood glucose regulation; des-n-octanoyl ghrelin; diabetic; feeding; ghrelin; glucose disposal; inhibitor/antagonist; insulin secretion; insulin sensitivity/resistance; mathematical model; novel strategies; obesity treatment; peptide hormone; research study; response; type I diabetic

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.

描述（由申请人提供）：生长素释放肽是一种肠道来源的酰化肽激素，可刺激生长激素和 ACTH 的分泌以及食欲生成。我们的中心论点是，生长素释放肽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 的分泌以保护去脂体重；减少运动活动以保存卡路里；以及调节分配，包括葡萄糖稳态。本申请的总体假设是（1）皮质醇和胰岛素是正常日常进食和禁食模式期间生长素释放肽释放的主要负调节因子，以及（2）这种特定的控制机制会因肥胖而改变，从而导致缺乏足够的生长素释放肽抑制会导致暴饮暴食。我们的实验室开发了针对完整活性酰基生长素释放肽和去酰基生长素释放肽的灵敏且特异的夹心测定法。使用这些测定，我们将实现以下具体目标： 1：确定健康瘦和肥胖成年人的脉动酰基和去酰基生长素释放肽分泌与血浆胰岛素、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 中直接干预的结果提供初步数据。此外，该数据将允许直接比较瘦与肥胖的相同关系。这些假设将使用生长素释放肽释放的最小数学模型进行测试（具体目标 4）。 2：确定皮质醇对生长素释放肽分泌的影响，以确定其在生长素释放肽分泌的昼夜变化中的作用。这些实验的结果将把皮质醇调节生长素释放肽的假设转化为最小的数学模型。 3：确定胰岛素是否抑制生长素释放肽分泌以及葡萄糖相关的生长素释放肽抑制是否由胰岛素介导。有人提出，胰岛素对生长素释放肽的抑制将取决于胰岛素敏感性/抗性，其方式与使用正常血糖胰岛素钳测量的葡萄糖处理类似。这些实验的结果将有助于将胰岛素调节生长素释放肽的假设转化为最小的数学模型。图4：确定瘦和肥胖受试者之间的生长素释放肽调节差异，并使用生长素释放肽调节的最小模型（MMGR）确定肥胖中生长素释放肽调节失调的机制。为了统一特定目标 2 和 3 中生长素释放肽、胰岛素和皮质醇之间的关系，我们将重建系统相互作用，并验证皮质醇和胰岛素构成生长素释放肽分泌的主要控制的生理假设的一致性，并确定控制生长素释放肽分泌的方式。肥胖时调节生长素释放肽分泌的整体发生了改变。我们的研究有望阐明生长素释放肽在肥胖发展中的潜在机制；这可能会带来治疗肥胖和相关疾病（例如糖尿病和代谢综合征）的新方法。 项目叙述：我们的研究预计将阐明生长素释放肽在肥胖发展中的潜在机制；这可能会带来治疗肥胖和相关疾病（例如糖尿病和代谢综合征）的新方法。