The Effect of Behavioral Weight Loss on Circulating Extracellular RNA

项目总结 并不是所有的肥胖者都有相同的代谢风险，不同类型和/或 体重减轻的程度改变了这一风险，这是有争议的。已经提出了遗传变异和代谢物图谱。 以解决肥胖者的代谢风险，尽管归因于遗传和代谢物的风险仍然很小。 因此，识别肥胖者代谢风险亚型的新标记物对于更好地 了解机制，确定减肥的滚动，并发现治疗靶向的途径。 血浆细胞外RNA(ex-RNAs)是参与肥胖患者跨器官交流的循环RNA， 表观遗传学调控脂肪细胞、肝细胞和骨骼中基因表达的复杂结构 肌肉强化代谢综合征。我们最近使用了RNA测序和高通量RT-qPCR来 确定血浆中与胰岛素抵抗、内脏和肝脏脂肪以及肥胖有关的前RNA 并验证了肥胖儿童人群中与胰岛素抵抗的相关性 在减肥手术后的极端减肥和糖尿病消退后表现出改变。 在美国，2016年肥胖率为39.8%，影响了约9330万成年人。尽管 手术减肥的好处，其广泛的风险排除了常规使用和绝大多数 肥胖和超重的人采用行为和饮食方法。目前尚不清楚这些事件的影响 炎症/表观遗传标记物上更常见的体重减轻和潜在复发模式 包括与代谢风险相关并促成代谢风险的前RNA。减肥保健品 随机对照试验是一项分两个阶段的研究，其中1032名超重或肥胖的成年人 在为期6个月的减肥计划(阶段1)中，至少4公斤的体重被随机分配到减肥维持中 干预(第二阶段)。测定行为减重与恢复对循环基因的影响 表达，我们建议；(1)根据行为重量确定循环EX-RNA的表达模式 减肥类似于减肥手术减肥；(2)确定前RNA的特定模式是否可以预测个体 持续的体重减轻与恢复；以及(3)获得初步蛋白质组数据以确定分子靶点。 这一提议的中心假设是已知的与代谢相关的血浆前RNA 症状在行为减轻后改变，有害的模式受 重量。 该提案将利用强大的现有数据，并利用已建立的技术和生物信息学 在我们的实验室中，应用转录转录方法来了解肥胖和 发现潜在的与非手术减肥相关的新介质。来自该项目的数据将是 用来扩展研究，在更广泛的人群中进行验证，有助于确定潜在的 风险分层和治疗探索的分子转录和蛋白质组学靶点。

PROJECT SUMMARY The notion that not all obese individuals are at the same metabolic risk and that different types and/or degrees of weight loss alter this risk is debated. Genetic variation and metabolite profiles have been proposed to resolve metabolic risk in the obese, though the risk attributed to genetics and metabolites remains small. Novel markers that identify sub-phenotypes of metabolic risk in the obese are therefore necessary to better understand mechanism, determine the roll of weight loss, and uncover pathways for therapeutic targeting. Plasma extracellular RNAs (ex-RNAs) are circulating RNAs involved in trans-organ communication in obesity, epigenetically regulating a complex architecture of gene expression in adipocytes, hepatocytes, and skeletal muscle to reinforce metabolic syndrome. We recently used RNA sequencing and high-throughput RT-qPCR to identify plasma ex-RNAs associated with insulin resistance, visceral and hepatic fat, and obesity in several thousand individuals and validated the association with insulin resistance in an obese pediatric population and demonstrated alteration after extreme weight loss and diabetes resolution post bariatric surgery. In the U.S., the 2016 prevalence of obesity was 39.8% and affected about 93.3 million adults. Despite the benefits of surgical weight loss, its extensive risks preclude routine utilization and the vast majority of obese and overweight individuals employ behavioral and dietary approaches. Unknown is the impact of these significantly more common patterns of weight loss and potential regain on inflammatory/epigenetic markers including ex-RNAs that are associated with and contribute to metabolic risk. The Weight Loss Maintenance Randomized Controlled Trial was a two-phase study in which 1032 overweight or obese adults who had lost at least 4 kg during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). To determine the impact of behavioral weight loss and regain on circulating gene expression, we propose to; (1) determine if patterns of circulating ex-RNA expression from behavioral weight loss are similar to bariatric surgical weight loss; (2) determine if specific patterns of ex-RNAs predict individuals with sustained weight loss vs. regain; and (3) obtain preliminary proteomic data to confirm molecular targets. The central hypothesis of this proposal is that plasma ex-RNAs known to be associated with metabolic syndrome are altered after behavioral weight loss and detrimental patterns are influenced by changes in weight. This proposal will leverage strong existing data and utilize technologies and bioinformatics established in our laboratory to apply a transcriptomic approach to understand the molecular underpinnings of obesity and uncover potential novel mediators associated with non-surgical weight loss. Data from this project would be utilized to expand the study with validation in a broader population, contributing to the identification of potential molecular transcriptomic and proteomic targets for risk stratification and therapeutic exploration.