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: 7557853
• 负责人: MICHAEL O THORNER
• 金额: $ 53.55万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7557853
• 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）：生长素蛋白是一种肠道衍生的酰化肽激素，可刺激生长激素和ACTH的分泌以及甲基化的肽以及眼药。我们的中心论点是，生长素蛋白可以通过以下方式保护哺乳动物免受饥饿的侵害：增加食欲和食物摄入量；增加GH的分泌以保护瘦体重；减少运动活性以保持卡路里；并调节分区，包括葡萄糖稳态。该应用的总体假设是（1）皮质醇和胰岛素是在正常的每日喂养和禁食模式中生长素释放的主要负调节剂，并且（2）这种特定的控制机制会因肥胖而改变，因此缺乏适当的抑制作用会导致过度造成过多的影响。我们的实验室已经开发了敏感的特异性三明治测定，用于完整的活性酰基葡萄肽和DES-acyl Ghrelin。使用这些测定法，我们将解决以下特定目的：1：确定健康瘦肉和肥胖成年人中胰岛素，皮质醇和生长激素的脉冲酰基酰基和乳糖酶分泌与血浆浓度之间的时间关系。这将提供初步数据，以预测特定目标2和3中直接干预的结果。此外，数据还可以直接比较精益与肥胖中的相同关系。该假设将使用最小的生长素释放数学模型来检验（特定目标4）。 2：确定皮质醇对生长素素分泌的作用，以确定其在昼夜分泌中的作用。这些实验的结果将把皮质醇调节的肽调节假设转化为最小数学模型。 3：确定胰岛素是否抑制生长素素分泌，以及与葡萄糖相关的生长素蛋白抑制是否由胰岛素介导。有人提出，胰岛素对生长素蛋白的抑制作用将依赖于胰岛素的敏感性/抗性，其方式与使用葡萄糖处理的方式相似，如使用尤利科血糖胰岛素夹一起测量的。这些实验的结果将有助于通过胰岛素调节变成最小的数学模型的假说。 4：确定瘦和肥胖受试者之间的生长素释放蛋白调节的差异，并确定使用最小的生长素蛋白调节模型（MMGR）来确定肥胖症中生长素蛋白失调的机制。 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.我们的研究预计将阐明涉及肥胖发育中的生长素的潜在机制。这可能会导致肥胖和相关疾病的治疗方法，例如糖尿病和代谢综合征。这可能会导致肥胖和相关疾病的治疗方法，例如糖尿病和代谢综合征。