The Effect of Behavioral Weight Loss on Circulating Extracellular RNA

项目摘要 并不是所有的肥胖个体都有相同的代谢风险，不同类型和/或 体重减轻的程度改变这种风险是有争议的。遗传变异和代谢产物谱已被提出 以解决肥胖者的代谢风险，尽管遗传和代谢物引起的风险仍然很小。 因此，有必要使用新的标记物来识别肥胖者代谢风险的亚表型， 了解机制，确定减肥的滚动，并揭示治疗靶向的途径。 血浆细胞外RNA（ex-RNA）是参与肥胖症跨器官通讯的循环RNA， 表观遗传学调节脂肪细胞、肝细胞和骨骼肌中基因表达的复杂结构 肌肉来强化代谢综合征。我们最近使用RNA测序和高通量RT-qPCR， 在几个人中鉴定与胰岛素抵抗、内脏和肝脏脂肪以及肥胖相关的血浆ex-RNA， 在1000名肥胖儿童中， 在减肥手术后极度减肥和糖尿病消退后显示出改变。 在美国，2016年肥胖患病率为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 肥胖和超重个体采用行为和饮食方法。未知的是这些影响 炎症/表观遗传标记物的体重减轻和潜在恢复模式明显更常见 包括与代谢风险相关并导致代谢风险的前RNA。减肥维护 随机对照试验是一项两阶段的研究，其中1032名超重或肥胖的成年人， 在为期6个月的减肥计划（第1阶段）中，至少4kg的患者被随机分配至减肥维持组 干预（第2阶段）。为了确定行为体重减轻和恢复对循环基因的影响， 表达，我们建议：（1）确定是否从行为体重循环前RNA表达模式 减肥类似于减肥手术减肥;（2）确定前RNA的特定模式是否预测个体 持续的体重减轻与恢复;和（3）获得初步的蛋白质组学数据以确认分子靶点。 该建议的中心假设是已知与代谢相关的血浆ex-RNA， 综合征的改变后，行为体重减轻和有害模式的影响， 重量. 该提案将利用现有的有力数据，并利用现有的技术和生物信息学。 在我们的实验室中，应用转录组学方法来了解肥胖的分子基础， 发现与非手术减肥相关的潜在新介质。该项目的数据将 用于扩展研究，在更广泛的人群中进行验证，有助于识别潜在的 分子转录组学和蛋白质组学的风险分层和治疗探索的目标。

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.