The Melanocortin-4 Receptor in Human Obesity

我们的长期目标是识别导致人类肥胖的基因突变，并了解它们 致病作用。 这一建议的重点是G蛋白偶联的黑素皮质素-4受体(MC4R)，这是一个在 中枢神经系统，并参与食物摄入量的调节。我们最初报告了第一个病例 人类肥胖与编码MC4R的基因突变有关。在上一个资助期，我们 广泛研究了严重肥胖儿童和成人中MC4R突变的流行率 人群；我们全面研究了50多种不同的导致肥胖的功能缺陷 MC4R突变；我们进一步鉴定了MC4R突变携带者的表型，并已开始 研究本病的基因分型与表型的关系。我们新的具体目标是： 1)扩大对MC4R基因座在人体能量平衡中作用的研究。我们将延长我们的 通过测试外部基因变异之间的关联来对整个MC4R基因座进行遗传学研究 与肥胖相关表型的MC4R转录单位和最小启动子在两个大病例- 对照研究和一个由3075人组成的表型良好的多基因队列。我们将特别集中精力 我们在MC4R基因座的进化保守区上的努力。 2)将肥胖成人MC4R突变携带者的基因-表型关系的研究扩展到 减肥手术后的结果。识别导致突变的基因的一个主要目标 人类常见的肥胖是提供更合理的治疗方法，最终通过对患者进行分层 分组，在这些分组中，不同治疗的有效性可以通过经验确定。减肥外科 是目前治疗病态肥胖症最有效的疗法。我们将使用一大批预期收集的队列 在2400名接受减肥手术的患者中，确定MC4R突变携带者是否有不同的 结果比非携带者要好。我们还将系统地研究小说造成的功能缺陷 在这个队列中检测到突变，并测试减肥手术后的结果是否与 MC4R突变携带者组内突变的功能特征。 3)研究黑素皮质素-4受体构筑活性的分子机制 通过其N端域。通过对肥胖相关N末端突变的系统研究 MC4R的结构域我们最近证明了该结构域保持了MC4R的结构活性 这种结构性活动在生理上是相关的。我们将进一步确定结构特征 通过其N-末端结构域促进受体的结构性激活。这些实验可能 导致新的策略，以药物靶向MC4R治疗肥胖症。

Our long-term objective is to identify gene mutations that cause obesity in humans and to understand their pathogenic effects. This proposal focuses on the G-protein coupled Melanocortin-4 Receptor (MC4R), a gene expressed in the central nervous system and implicated in the regulation of food intake. We had initially reported the first case of human obesity linked to a mutation in the gene encoding the MC4R. In the previous funding period we have extensively studied the prevalence of MC4R mutations in both severely obese children and adult populations; we have comprehensively studied the functional defects of over 50 different obesity causing MC4R mutations; we have further characterized the phenotype of MC4R mutation carriers and have started to study the genotype-phenotype relationship within this disease. Our new specific aims are: 1) To extend the study of the role of the MC4R locus in energy homeostasis in humans. We will extend our genetic studies to the entire MC4R locus by testing for an association between genetic variations outside of the transcriptional unit and minimal promoter of MC4R with obesity related phenotypes in both a large case- control study and a well phenotyped multi-ethinic cohort of 3,075 individuals. We will especially concentrate our efforts on evolutionary conserved regions at the MC4R locus. 2) To extend the study of the genotype-phenotype relationship in obese adult MC4R mutation carriers to the outcome after bariatric surgery. A major goal of identifying genes in which mutations are responsible for common human obesity is to provide more rational approaches to therapy, eventually by stratifying patients into groups in which the effectiveness of different treatments can be determined empirically. Bariatric surgery is currently the most effective therapy for morbid obesity. We will use a large prospectively collected cohort of 2400 patients undergoing bariatric surgery to determine if MC4R mutation carriers have a different outcome than non-carriers. We will also systematically study the functional defects caused by novel mutations detected in this cohort and test if the outcome after bariatric surgery can be correlated to the functional characteristics of the mutations within the group of MC4R mutation carriers. 3) To examine the molecular mechanisms involved in the constitutive activity of the melanocortin-4 receptor by its N-terminal Domain. Through the systematic study of obesity-associated mutations in the N-terminal domain of MC4R we have recently demonstrated that this domain maintains the constitutive activity of MC4R and that this constitutive activity is physiologically relevant. We will further identify the structural features contributing to the constitutive activation the receptor by its N-terminal domain. These experiments could lead to new strategies to pharmacologically target MC4R for the treatment of obesity.