Structure and Regulation of Ghrelin in Obesity

描述(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央中心之间的复杂相互作用、脂肪细胞衍生蛋白和肠道衍生蛋白组成。Ghrelin是最近发现的一种胃肠激素，最初被发现是生长激素促分泌素受体的内源性配体。在动物身上，Ghrelin是一种有效的Orexigen，可以诱导肥胖，在人类身上也被证明可以刺激食欲。Ghrelin在已知的激素中是独一无二的，因为它有一个连接在蛋白质骨架上的酰基，而这个酰基必须存在才能正常活动。胃促生长素水平受到膳食的强烈抑制，基础水平与胰岛素抵抗有关。几项研究表明，常量营养素含量不同的膳食对胃促生长素的抑制作用存在差异。这些差异可能是由于一些共同分泌的激素(包括胰岛素、胰升糖素样肽1或YY肽)的反应而发生的，并对Ghrelin在维持肥胖状态中的作用具有重要意义。以前的研究主要是通过测量总的免疫反应水平来检验Ghrelin的调节，其中包括活性和非活性形式的Ghrelin。然而，Ghrelin总量的变化可能不会反映对活性Ghrelin水平的影响；很少有研究试图表征Ghrelin蛋白的结构(蛋白质骨架的长度，脂肪酸配体的类型)，这也可能影响Ghrelin受体信号传递。在已知遗传性肥胖的受试者中独一无二的是，那些患有Prader-Willi综合征(PWS)的人发现总Ghrelin水平升高。根据这种Ghrelin的结构，这些高水平可能是导致这种综合征的贪婪食欲的原因之一。因此，这里建议的研究包括描述PWS和对照中Ghrelin的结构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，确定特定的餐后激素对Ghrelin水平和结构的影响，以及胰岛素敏感性的改善是否在决定糖耐量受损受试者的基础和膳食相关Ghrelin抑制方面发挥独立作用。总之，这项建议的总体目标是利用最先进的方法研究营养和药物调节对Ghrelin水平和结构的影响。这些研究的结果将通过阐明瘦人和肥胖者胃促生长素水平和结构的调节，拓宽我们对参与体重调节的脑-肠轴的理解。

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.