The Effect of Behavioral Weight Loss on Circulating Extracellular RNA

行为减肥对循环细胞外 RNA 的影响

• 批准号: 10041786
• 负责人: JANE E Freedman
• 金额: $ 12.56万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041786
• 关键词: Adipocytes; Adult; Affect; African American; Architecture; Bariatrics; Behavioral; Bioinformatics; Biological Markers; Biological Process; Blood Circulation; Body Weight decreased; Body mass index; Brown Fat; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Code; Communication; Complex; Data; Diabetes Mellitus; Diet; Dyslipidemias; Epigenetic Process; Fatty acid glycerol esters; Framingham Heart Study; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Hepatic; Hepatocyte; Heterogeneity; Hypertension; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intervention; Laboratories; Maintenance; Measurement; Measures; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; MicroRNAs; Molecular; Molecular Target; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Operative Surgical Procedures; Organ; Overweight; Participant; Pathway Analysis; Pathway interactions; Pattern; Phase; Phenotype; Plasma; Population; Prevalence; Proteins; Proteomics; RNA; Randomized; Randomized Controlled Trials; Regulation; Resolution; Risk; Risk stratification; Sampling; Skeletal Muscle; Small RNA; Structure of beta Cell of islet; Technology; Therapeutic; Validation; Visceral; Visit; Weight; Woman; adult obesity; bariatric surgery; biological systems; clinical biomarkers; clinical investigation; dietary approach; epigenetic marker; ethnic diversity; extracellular; high risk; metabolic phenotype; metabolomics; novel; novel marker; obesity in children; programs; public health relevance; racial diversity; response; screening; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics; weight loss program

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.

项目摘要 并非所有肥胖个体都处于代谢风险和不同类型和/或 体重减轻程度改变了这种风险。已经提出了遗传变异和代谢物谱 解决肥胖的代谢风险，尽管归因于遗传学和代谢产物的风险仍然很小。 因此，有必要在肥胖中识别代谢风险的亚表格型的新颖标记是为了改善的 了解机制，确定体重减轻卷，并发现治疗靶向的途径。 血浆细胞外RNA（EX-RNA）是循环的RNA，参与肥胖中的跨器官通信， 表观遗传调节脂肪细胞，肝细胞和骨骼中基因表达的复杂结构 肌肉增强代谢综合征。我们最近使用RNA测序和高通量RT-QPCR 鉴定与胰岛素抵抗，内脏和肝脂肪相关的血浆EX-RNA，并在几种 成千上万的人，并在肥胖的儿科人群中验证了与胰岛素抵抗的关联， 体重减轻后表现出改变，减肥手术后的糖尿病分辨率发生了变化。 在美国，2016年肥胖症患病率为39.8％，约有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利用，绝大多数 肥胖和超重的人采用行为和饮食方法。未知是这些的影响 体重减轻和潜在的炎症/表观遗传标记的潜力更为常见的模式 包括与新陈代谢风险相关的前RNA。减肥维持 随机对照试验是一项两阶段的研究，其中1032个超重或肥胖的成年人在 在6个月的减肥计划（第1阶段）期间，至少4公斤被随机分为减肥维护 干预（第2阶段）。确定行为减肥的影响并恢复对循环基因的影响 表达，我们建议； （1）确定行为重量的循环前RNA表达的模式是否 损失类似于减肥手术体重减轻； （2）确定EX-RNA的特定模式是否预测个体 持续减肥与恢复； （3）获得初步蛋白质组学数据以确认分子靶标。 该提议的中心假设是，已知与代谢相关的血浆rna 行为体重减轻和有害模式后，综合症会改变 重量。 该建议将利用强大的现有数据，并利用建立的技术和生物信息学 在我们的实验室中，采用转录组方法来了解肥胖和 发现潜在的新型介体与非手术减肥有关。这个项目的数据将是 利用在更广泛的人群中通过验证扩展研究，有助于识别潜力 用于风险分层和治疗探索的分子转录组和蛋白质组学靶标。