Functional Selectivity in MC4R Signaling

描述(申请人提供)：肥胖是发达国家面临的最普遍的健康问题。肥胖是一种衡量肥胖程度的指标，它具有很高的遗传性。研究遗传性肥胖症对受影响的个体很重要，有助于了解正常的代谢途径。神经系统中的黑素皮质素途径在调节食物摄入、能量消耗和新陈代谢方面起着核心作用。黑素皮质素4受体(MC4R)突变是最常见的单基因肥胖形式，在1-5%的肥胖者中发现。我们筛选了一组接受Roux-en-Y胃旁路(RYGB)手术的严重肥胖患者，发现有常见和罕见的MC4R变异。在对照组中没有发现罕见的MC4R变异。在RYGB队列中，MC4R的特定改变与不同的减肥结果相关。鉴于罕见的MC4R变异与肥胖之间的强烈关联，我们认为MC4R在细胞信号中的特定变化可以影响体重减轻。传统上，MC4R与cAMP信号联系在一起。在100多种不同的与肥胖相关的MC4R变体中，许多都显示出正常的配体结合、表达和cAMP信号。因此，突变体体内肥胖表型与cAMP信号之间的相关性尚不完善。在我们的初步数据中，我们发现特定的突变和配体可以改变MC4R对不同途径的相关信号。我们认为，MC4R下游的其他信号通路和由此产生的生理输出在体重减轻和体重增加方面发挥着关键作用。为了验证这一假说，第一个目的是研究神经元MC4R在各种天然配体刺激下与不同途径的偶联。我们将使用定量的、控制良好的方法，研究神经元中不同路径的天然MC4R信号。在第二个目标中，我们将测试各种自然发生的突变体对每条途径的信号，并确定控制它们差异耦合的机制。使用电生理学方法，我们将测试不同的信号如何通过调节特定的离子电流来调节神经元的活动。最后，我们将确定与每个信号通路相关的基因表达的变化。这些研究将确定在体重增加中至关重要的MC4R信号通路，并将有助于确定特定治疗的新靶点。

DESCRIPTION (provided by applicant): Obesity is the most prevalent health problem facing developed countries. Adiposity, a measure of fatness, is highly heritable. Studying genetic obesity disorders is important to the affected individual and helps in understanding normal metabolic pathways. The melanocortin pathway in the nervous system plays a central role in regulating food intake, energy expenditure, and metabolism. Mutations in the melanocortin 4 receptor (MC4R) are the most common form of monogenic obesity, found in 1-5% of obese people. We screened a cohort of severely obese patients undergoing Roux-en-Y gastric bypass (RYGB) surgery and found individuals with common and rare MC4R variants. There were no rare MC4R variants among control subjects. In the RYGB cohort, specific alterations in MC4R were associated with different weight loss outcomes. Given the strong association between rare MC4R variants and obesity, we believe that specific changes in cellular signaling by MC4R can affect weight loss. MC4R has traditionally been linked to cAMP signaling. Of the more than 100 different reported MC4R variants associated with obesity, many show normal ligand binding, expression and cAMP signaling. Therefore, the correlation between the in vivo obesity phenotype and cAMP signaling of the mutants is imperfect. In our preliminary data, we find that specific mutations and ligands can change relative signaling by MC4R to different pathways. We believe other signaling pathways downstream from MC4R and the resulting physiological output play critical roles in weight loss and weight gain. To test this hypothesis, the first aim is to stdy coupling of neuronal MC4R to different pathways when stimulated by various natural ligands. We will use quantitative, well-controlled approaches, to study native MC4R signaling to different pathways in neurons. In the second aim, we will test signaling by various naturally occurring mutants to each pathway, and determine the mechanisms that control their differential coupling. Using electrophysiological approaches, we will test how different signals regulate neuronal activity by modulating specific ionic currents. Finally, we will identify changes in gene expressio associated with each signaling pathway. These studies will identify MC4R signaling pathways that are critical in weight gain and will help identify new targets for specific therapies for obesty.