Adipose stem cells' niche in obesity

脂肪干细胞在肥胖中的作用

• 批准号: 10363226
• 负责人: Niketa A. Patel
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363226
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Afghanistan; Biochemical; Biology; Blood Vessels; Body mass index; COVID-19; COVID-19 pandemic; Cardiovascular Diseases; Caring; Cause of Death; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Chronic Disease; Clinical; Core Facility; Data; Department of Defense; Development; Diabetes Mellitus; Disease; Endocrine; Evaluation; Expenditure; Fatality rate; Genes; Genetic; Genomic medicine; Glucocorticoid Receptor; Goals; Guidelines; Gulf War; Health; Health Care Costs; Homeostasis; Human; Hyperplasia; Hypertrophy; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Iraq; Knowledge; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolic stress; Metabolic syndrome; Metabolism; Molecular; Morbid Obesity; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonsense-Mediated Decay; Obese Mice; Obesity; Overweight; Pathology; Pathway interactions; Pattern; Physiological; Plasmids; Population; Public Health; RNA; Regulator Genes; Reporting; Research; Research Personnel; Risk Factors; Role; Severities; Small Interfering RNA; Thinness; Tissue Differentiation; United States Department of Veterans Affairs; United States National Center for Health Statistics; Untranslated RNA; Veterans; Woman; Work; beneficiary; comorbidity; diet-induced obesity; experience; experimental study; frontier; genetic makeup; growth arrest specific transcript 5; in vitro Model; in vivo; individual patient; insulin signaling; interdisciplinary approach; lipid biosynthesis; military veteran; mortality; mouse model; novel therapeutics; obese patients; obese person; obesity treatment; overexpression; pre-clinical; prevent; receptor; screening; small molecule; small molecule therapeutics; statistics; stem cell biomarkers; stem cell differentiation; stem cell niche; stem cells; tool; transcriptomics

Obesity continues to escalate as a significant public health problem and as the leading preventable cause of death. Stark data from COVID19 pandemic shows obesity is an independent risk factor of severity with 33% mortality rate. Obesity per se is not fatal but is the major health risk factor promoting severe diseases including cardiovascular diseases, type 2 diabetes mellitus, and certain cancers. 42% of adult population in US is obese (CDC NCHS report 2020). Healthcare costs related to obesity account for greater than 10% of total US medical expenditures and has risen to $254 billion per year (1). Alarmingly 78% of the Veteran population is obese, a notably higher percent compared to civilian population(2). Adipose tissue is an important endocrine regulator of energy homeostasis and metabolism. During adipogenesis, the adipose stem cells (ASC) differentiate into adipocytes and replenish the body’s need for new adipocytes. Normal adiposity is exaggerated in obesity and is accompanied by adipocyte hyperplasia and hypertrophy. Previously this lab demonstrated that obesity changes the human adipose stem cells’ niche such that it promotes a microenvironment conducive to developing obesity-associated comorbidities. A significant finding was that the expression of long noncoding RNAs (lncRNAs) differed in the obese ASC compared to lean subjects which contributed to the aberrant metabolic processes, insulin resistance and chronic low-grade inflammation observed in obesity. Using an unbiased transcriptomic screening, this lab identified lncRNA GAS5 as an important regulatory gene that is depleted in human obese adipose tissue, ASC and mature adipocytes compared to lean. Prior research has demonstrated that GAS5 regulates insulin receptor and glucocorticoid receptor mediated pathways. However, the importance and impact of low GAS5 levels on the metabolic pathways in obese adipocytes has not yet been thoroughly investigated. Hence, it is hypothesized that low levels of GAS5 substantially contributes to the manifestation of comorbidities associated with obesity. Towards the overarching goal to determine if GAS5 supports healthy adipocytes, the proposal will evaluate the underlying mechanisms and role of GAS5 in human obese ASC and adipocytes using a multi-disciplinary approach including pre-clinical, physiological, cellular and biochemical experiments. Specific Aim 1: Determine the role of GAS5 in ASC and adipocytes: It is hypothesized that manipulating GAS5 levels will affect the metabolic health of ASC and adipocytes. GAS5 siRNA or over-expression plasmid will be used to evaluate the genetic and metabolic parameters pertaining to adipocyte health and function. Specific Aim 2: Elucidate molecular mechanisms regulated by GAS5 in obese adipocytes: GAS5 levels are low in ASC and adipose tissue in obesity. A small molecule that stabilizes GAS5 has been recently developed. It is hypothesized that stabilizing GAS5 levels could alleviate the metabolic stress and the project will use this compound as a molecular tool to determine the underlying molecular mechanisms with functional readouts. Specific Aim 3: Investigate the impact of GAS5 stabilization in vivo in an obese mouse model: The in vitro data shows that the small molecule targeting GAS5 increases IR levels, restores insulin signaling and regulates GR-target genes. This aim will systematically elucidate the physiological effects of stabilizing GAS5 with the novel therapeutic in a diet-induced obese mouse model. Overall, this project fills significant gaps in knowledge to understand the role of lncRNAs in the metabolic processes affecting adipose tissue in obesity in humans. Identification of GAS5 as a druggable RNA target in a metabolic disease has led to successfully develop a small molecule therapeutic that stabilizes GAS5 (a frontier in genomic medicine) with a high potential of promoting the metabolic health of ASC and adipocytes in obesity. This project will have a considerable impact to prevent or treat metabolic dysfunction associated with obesity, thus impeding the ascent of obesity as the most preventable cause of death.

肥胖症继续升级为重大公共卫生问题，并作为可预防的主要原因 死亡。 Covid19大流行的Stark数据表明，肥胖是严重程度的独立危险因素，为33％ 死亡率。肥胖本身并不是致命的，而是促进严重疾病的主要健康危险因素 心血管疾病，2型糖尿病和某些癌症。美国42％的成年人口是肥胖 （CDC NCHS报告2020）。与肥胖有关的医疗保健费用超过美国总数的10％ 医疗支出，每年增加到2540亿美元（1）。令人震惊的是，有78％的退伍军人人口是 肥胖，与平民相比，百分比明显高（2）。 脂肪组织是能量稳态和代谢的重要内分泌调节剂。期间 脂肪生成，脂肪干细胞（ASC）分化为脂肪细胞，并复制身体的需求 新的脂肪细胞。肥胖症中正常的肥胖被夸大，并伴有脂肪细胞增生 和肥大。以前，该实验室表明肥胖改变了人脂肪干细胞的利基 因此，它促进了一个微环境导电，以发展与肥胖相关的合并症。一个 重大发现是肥胖ASC中长的非编码RNA（LNCRNA）的表达 与有助于异常代谢过程，胰岛素抵抗和 在肥胖症中观察到慢性低度炎症。使用公正的转录组筛选，该实验室 将lncrna gas5鉴定为一个重要的调节基因，在人类肥胖脂肪组织中耗尽， 与瘦肉相比，ASC和成熟的脂肪细胞。先前的研究表明，GAS5调节胰岛素 受体和糖皮质激素受体介导的途径。但是，低气5的重要性和影响 肥胖脂肪细胞中代谢途径的水平尚未得到彻底研究。因此，是 假设低水平的气5基本上有助于合并症的表现 与肥胖有关。达到总体目标，以确定GAS5是否支持健康的脂肪细胞， 提案将评估GAS5在人肥胖ASC和脂肪细胞中的基本机制和作用 使用多学科方法，包括临床前，物理，细胞和生化实验。 特定目标1：确定GAS5在ASC和脂肪细胞中的作用：假设操纵 GAS5水平将影响ASC和脂肪细胞的代谢健康。 GAS5 siRNA或过表达质粒 将用于评估与脂肪细胞健康和功能有关的遗传和代谢参数。 特定目的2：阐明肥胖脂肪细胞中气5调节的分子机制：GAS5水平为 肥胖症中的ASC和脂肪组织低。最近已经开发了一种稳定气5的小分子。 假设稳定GAS5水平可以减轻代谢压力，该项目将使用此功能 化合物是一种分子工具，可确定具有功能读数的基本分子机制。 特定目的3：研究肥胖小鼠模型中GAS5稳定体体内的影响：体外 数据表明，针对GAS5的小分子增加了IR水平，恢复胰岛素信号传导和 调节gr靶基因。这个目标将系统地阐明稳定气5的物理影响 在饮食引起的肥胖小鼠模型中的新疗法。 总体而言，该项目填补了了解LNCRNA在 影响人类肥胖症脂肪组织的代谢过程。识别GAS5作为可吸毒的 代谢性疾病中的RNA靶标导致成功发展了一种稳定的小分子疗法 GAS5（基因组医学领域的前沿）具有促进ASC代谢健康的高潜力 肥胖中的脂肪细胞。该项目将对预防或治疗代谢功能障碍产生重大影响 与肥胖有关，因此阻碍了肥胖症的上升为最可预防的死亡原因。