The Effect of Behavioral Weight Loss on Circulating Extracellular RNA

行为减肥对循环细胞外 RNA 的影响

基本信息

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
项目类别：
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

项目摘要

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.

项目概要并非所有肥胖者都处于相同的代谢风险并且不同类型和/或体重减轻的程度会改变这种风险，这一点存在争议。已提出遗传变异和代谢谱解决肥胖者的代谢风险，尽管遗传和代谢物造成的风险仍然很小。因此，需要识别肥胖者代谢风险亚表型的新标记物，以更好地了解机制、确定减肥效果并揭示治疗目标的途径。血浆细胞外 RNA (ex-RNA) 是参与肥胖跨器官通讯的循环 RNA，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以强化代谢综合症。我们最近使用 RNA 测序和高通量 RT-qPCR 来鉴定与胰岛素抵抗、内脏和肝脏脂肪以及肥胖相关的血浆 ex-RNA 数千人并验证了肥胖儿科人群与胰岛素抵抗的关系，在减肥手术后极度减肥和糖尿病缓解后表现出变化。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，其广泛的风险妨碍了常规使用，并且绝大多数肥胖和超重的人采用行为和饮食方法。这些影响尚不清楚明显更常见的体重减轻模式和炎症/表观遗传标记的潜在恢复模式包括与代谢风险相关并导致代谢风险的 ex-RNA。减肥保养随机对照试验是一项两阶段研究，其中 1032 名超重或肥胖的成年人在在为期 6 个月的减肥计划（第一阶段）期间减重至少 4 公斤被随机分配至减肥维持组干预（第二阶段）。确定行为减肥和恢复对循环基因的影响表达，我们建议； (1) 确定循环 ex-RNA 表达模式是否来自行为体重减肥效果与减肥手术减肥相似； (2) 确定 ex-RNA 的特定模式是否可以预测个体体重持续减轻与恢复； (3) 获得初步的蛋白质组数据以确认分子靶标。该提案的中心假设是已知血浆 ex-RNA 与代谢相关行为减肥后，综合症会发生改变，有害模式会受到行为减肥变化的影响重量。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。该项目的数据将是用于扩大研究范围并在更广泛的人群中进行验证，有助于识别潜在的用于风险分层和治疗探索的分子转录组和蛋白质组目标。