Structure and Regulation of Ghrelin in Obesity

肥胖中 Ghrelin 的结构和调节

• 批准号: 7586816
• 负责人: JONATHAN Q. PURNELL
• 金额: $ 26.99万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586816
• 关键词: 2,4-thiazolidinedione; Adipocytes; Affect; Animals; Arts; Biological; Biological Assay; Blood; Body Weight; Brain; Brain Stem; Carbohydrates; Characteristics; Complex; Desire for food; Diet; Energy Metabolism; Euglycemic Clamping; Fasting; Fatty Acids; Fatty acid glycerol esters; Genetic; Glucose Clamp; Goals; High Pressure Liquid Chromatography; Hormones; Human; Hypothalamic structure; Individual; Infusion procedures; Insulin; Insulin Resistance; Intravenous infusion procedures; Length; Ligands; Link; Macronutrients Nutrition; Maintenance; Mass Spectrum Analysis; Measurement; Measures; Medium chain triglycerides; Methods; Nutrient; Obesity; Overweight; Peptide YY; Peripheral; Play; Prader-Willi Syndrome; Proteins; Receptor Signaling; Regulation; Research Personnel; Role; Saline; Structure; Syndrome; System; Thiazolidinediones; Vertebral column; acyl group; cell growth regulation; feeding; ghrelin; ghrelin receptor; glucagon-like peptide 1; growth hormone secretagogue receptor; impaired glucose tolerance; improved; increased appetite; insight; insulin sensitivity; programs; response; rosiglitazone

DESCRIPTION (provided by applicant): Obesity results from dysregulation of central and peripheral systems governing appetite and energy expenditure. These systems are made up of complex interactions between central centers in the hypothalamus and brainstem, adipocyte-derived proteins, and gut-derived proteins. Ghrelin is a recently described gut hormone originally discovered as an endogenous ligand for the growth hormone secretagogue receptor. In animals, ghrelin is a potent orexigen that can induce obesity and in humans has also been shown to stimulate appetite. Ghrelin is unique among known hormones in that it has an acyl group attached to a protein backbone, and this acyl group must be present for normal activity. Ghrelin levels are acutely suppressed by meals and basal levels are linked with insulin resistance. Several studies have shown differences in ghrelin suppressibility by meals that vary in macronutrient content. These differences could occur in response to a number of co-secreted hormones (including insulin, glucagon-like peptide 1, or peptide YY), and have important implications for the role of ghrelin in maintenance of the obese state. Previous studies have examined ghrelin regulation by predominantly measuring total immunoreactive levels, which includes both active and inactive forms of ghrelin. However, changes in total ghrelin may not reflect effects on active ghrelin levels; and few studies have attempted to characterize the structure of ghrelin protein (length of the protein backbone, types of fatty acid ligands), which could also affect ghrelin receptor signaling. Unique in subjects with known genetic obesity, those with Prader-Willi Syndrome (PWS) have found to have elevated levels of total ghrelin. Depending on the structure of this ghrelin, these high levels may be contributing to the voracious appetite characteristic of this syndrome. Studies proposed here, therefore, include the characterization of ghrelin's structure in PWS and controls to provide insight into its biological activity and cellular regulation, clarification of the nutrient regulation of ghrelin levels and structure in these groups, determine the effects of specific postprandial hormones on ghrelin levels and structure, and whether improvement in insulin sensitivity plays an independent role in the determining basal and meal-related ghrelin suppression in subjects with impaired glucose tolerance. In summary, the overall goals of this proposal are to study the effect of nutrient and pharmacological regulation on both ghrelin levels and structure using state-of-the-art methods. Results from these studies will broaden our understanding of the brain-gut axis involved in body weight regulation by clarifying the regulation of ghrelin levels and structure in lean and obese individuals.

描述（由申请人提供）：肥胖是由控制食欲和能量消耗的中枢和外周系统失调引起的。这些系统由下丘脑和脑干中的中枢中心、脂肪细胞衍生的蛋白质和肠衍生的蛋白质之间的复杂相互作用组成。Ghrelin是最近描述的一种肠道激素，最初被发现为生长激素促分泌素受体的内源性配体。在动物中，生长激素释放肽是一种有效的食欲素，可以诱导肥胖，在人类中也被证明可以刺激食欲。Ghrelin在已知的激素中是独特的，因为它具有连接到蛋白质骨架的酰基，并且该酰基必须存在才能正常活动。胃饥饿素水平被食物严重抑制，基础水平与胰岛素抵抗有关。几项研究表明，大量营养素含量不同的膳食对胃饥饿素的抑制作用存在差异。这些差异可能发生在对许多共同分泌的激素（包括胰岛素、胰高血糖素样肽1或肽YY）的响应中，并且对生长激素释放肽在维持肥胖状态中的作用具有重要意义。以前的研究主要通过测量总的免疫反应水平来检查ghrelin调节，其中包括ghrelin的活性和非活性形式。然而，总生长激素释放肽的变化可能不反映对活性生长激素释放肽水平的影响;很少有研究试图表征生长激素释放肽蛋白的结构（蛋白骨架的长度，脂肪酸配体的类型），这也可能影响生长激素释放肽受体信号传导。在已知遗传性肥胖的受试者中，普拉德-威利综合征（PWS）患者的总生长激素释放肽水平升高。根据这种生长激素释放肽的结构，这些高水平可能有助于这种综合征的贪婪食欲特征。因此，本文提出的研究包括PWS和对照中ghrelin结构的表征，以提供对其生物活性和细胞调节的洞察，澄清这些组中ghrelin水平和结构的营养调节，确定特定餐后激素对ghrelin水平和结构的影响，以及胰岛素敏感性的改善是否在确定葡萄糖耐量受损受试者中基础和膳食相关的生长素释放肽抑制中起独立作用。总之，本提案的总体目标是使用最先进的方法研究营养和药理学调节对ghrelin水平和结构的影响。这些研究的结果将通过阐明瘦和肥胖个体中ghrelin水平和结构的调节来拓宽我们对体重调节所涉及的脑-肠轴的理解。