Obesity and Inflammation

肥胖和炎症

• 批准号: 7593617
• 负责人: Louis Simchowitz
• 金额: $ 32万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593617
• 关键词: Adherence; Adipocytes; Adipose tissue; Admission activity; Affect; Air; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Biological Markers; Biopsy; Blood Tests; Body Composition; Body Weight; Body Weight decreased; Caloric Restriction; Candidate Disease Gene; Cardiovascular Diseases; Cataloging; Catalogs; Characteristics; Chronic; Clinical; Clinical Protocols; Condition; DNA; Data; Development; Dietary Intervention; Dinoprostone; Eicosanoids; Endocrine System Diseases; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemic; Event; Extracellular Fluid; Future; Gene Expression; Genes; Genetic Transcription; Genomics; Genotype; Health Care Costs; Hospitals; Human; Hypertension; Indirect Calorimetry; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inpatients; Interleukin-6; Intramural Research Program; Invasive; Lead; Leptin; Leukotriene B4; Light; Liquid Chromatography; Literature; Malignant Neoplasms; Measurement; Mediator of activation protein; Metabolic; Methods; Microarray Analysis; Microdialysis; Modality; Morbidity - disease rate; Names; Nature; Numbers; Obesity; Omega-3 Fatty Acids; Overweight; Participant; Patients; Pattern; Personal Satisfaction; Personality; Phenotype; Physiological; Play; Plethysmography; Population; Procedures; Process; Protocols documentation; Public Health; Rate; Research Design; Role; Sampling; Series; Serum; Societies; Source; Specimen; Standards of Weights and Measures; Stromal Cells; Study Subject; Techniques; Testing; Thinking; Time; Tissue Sample; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Weight; Work; adipokines; adiponectin; concept; cytokine; diabetes risk; dietary restriction; human TNF protein; in vivo; indexing; insight; insulin sensitivity; intravenous glucose tolerance test; lipoxin A4; macrophage; man; mortality; novel; novel therapeutics; response; subcutaneous; tandem mass spectrometry; volunteer

Obesity is a global public health problem of epidemic proportions. It is the source of considerable morbidity and early mortality in the U.S. and is associated with increased risk of diabetes, hypertension, cardiovascular disease, and cancer to name a few. All segments of the population are affected and the burden to society, in terms of general well-being and healthcare costs, is tremendous. In recent years, new and evolving concepts have emerged regarding obesity as a chronic endocrine disorder of inflammation. Moreover, a small, but growing body of evidence both in animals and in man indicates that obesity per se alters the profile of a constellation of genes and that at least some of these changes in biomarkers of inflammation and gene expression can be reversed by weight loss. The data in humans is rather scant, with just a handful of articles on this subject in the current literature. In this clinical protocol, we propose to extend the early and evolving work in humans by testing and reconfirming the idea that a particular set of genes is activated (or deactivated) in overweight subjects using standard microarray techniques on samples of subcutaneous adipose tissue derived from biopsies. In addition, we will broaden and extend this work by studying the local adipose tissue microenvironment in vivo by means of a microdialysis procedure, a minimally invasive technique that allows the serial determination of components of the extracellular fluid under physiological conditions. The role of a number of adipokines (such as leptin and adiponectin) and inflammatory mediatorscytokines (e.g., TNF-alpha, IL-6, and eicosanoids such as Prostaglandin E2, Lipoxin A4, and Leukotriene B4) will be analyzed using sensitive Liquid Chromatography-Tandem Mass Spectrometry and ELISA methods. The study design incorporates two basic objectives: (a) Comparison of Non-Overweight Controls vs. Overweight Subjects at Baseline and (b) Correlation of changes in Overweight patients over time as they lose weight through a calorie-restricted diet. To these ends, 30 Non-Overweight Controls (BMI 19.0 to 24.9) and 80 Overweight Subjects (BMI 25.0 to 45.0) will be enrolled. Baseline studies, to be obtained on all participants include: routine and specialized blood tests, anthropometric indices, body composition by air-displacement plethysmography, indirect calorimetry, intravenous glucose tolerance test as an index of insulin sensitivity, subcutaneous adipose tissue microdialysis procedures to sample the local microenvironment for various adipokines, cytokines, and eicosanoid mediators of inflammation, and subcutaneous adipose tissue biopsy for analysis of gene expression using standard microarray techniques. These procedures will require an overnight hospital admission to the Clinical Center. Overweight Subjects will then be prescribed a calorie-restricted diet and followed for one year. They will undergo the same repeat studies and procedures outlined above at regular, 3-month intervals so as to assess serial changes in the various parameters and to provide correlative data with the degree and rate of weight loss achieved. Studies are currently in progress as we have just begun to enroll patients in the protocol. The first few study volunteers have successfully completed their first inpatient admissions to the Metabolic Unit of the Clinical Center. Taken together, these studies should shed light and provide fundamental insights into the nature of the altered gene expression and release of inflammatory cytokines and other mediators that characterize the overweight state and the dynamic series of events that take place when dietary intervention leads to weight loss. It is anticipated that a number of these changes will relate to macrophages and known inflammatory markers though doubtless there are other important leads yet to be discovered. Thus, our hope is that such studies will ultimately lead to the identification of novel genes that underlie the important metabolic derangements associated with obesity and their response to different treatment modalities.

肥胖症是一个全球性的流行病公共卫生问题。 它是美国相当大的发病率和早期死亡率的来源，并且与糖尿病、高血压、心血管疾病和癌症的风险增加相关。 人口的各个部分都受到影响，在一般福利和医疗保健费用方面给社会带来巨大负担。 近年来，出现了新的和不断发展的概念，认为肥胖是一种慢性炎症内分泌紊乱。 此外，在动物和人类中，一个小的，但越来越多的证据表明，肥胖本身改变了一系列基因的轮廓，至少有一些炎症和基因表达的生物标志物的变化可以通过减肥来逆转。 人类的数据相当少，在当前的文献中只有少数关于这个主题的文章。 在这个临床协议中，我们建议通过测试和重新确认的想法，即一组特定的基因被激活（或失活）在超重的受试者使用标准的微阵列技术对来自活检的皮下脂肪组织样本扩展早期和不断发展的工作在人类。 此外，我们将扩大和扩展这项工作，通过微透析程序，微创技术，允许在生理条件下的细胞外液的成分的系列测定的装置在体内研究局部脂肪组织微环境。 许多脂肪因子（如瘦素和脂联素）和炎症介质细胞因子（如，将使用灵敏的液相色谱-串联质谱法和ELISA方法分析TNF-α、IL-6和类花生酸（如前列腺素E2、脂氧素A4和白三烯B4）。 研究设计包含两个基本目标： (a)基线时非超重对照组与超重受试者的比较， (b)超重患者通过限制热量饮食减肥时随时间变化的相关性。 为此，将入组30例非超重对照（BMI 19.0 - 24.9）和80例超重受试者（BMI 25.0 - 45.0）。 对所有参与者进行的基线研究包括：常规和专门的血液测试、人体测量指数、通过空气置换体积描记法的身体组成、间接量热法、作为胰岛素敏感性指数的静脉内葡萄糖耐量测试、皮下脂肪组织微透析程序以针对各种脂肪因子、细胞因子和炎症的类花生酸介质对局部微环境进行取样，和皮下脂肪组织活组织检查以使用标准微阵列技术分析基因表达。 这些程序将需要在临床中心住院过夜。 超重受试者随后将接受热量限制饮食，并随访一年。 他们将定期进行上述相同的重复研究和程序，间隔3个月，以评估各种参数的连续变化，并提供与体重减轻程度和速度相关的数据。 研究目前正在进行中，因为我们刚刚开始在方案中招募患者。 最初的几名研究志愿者已成功完成了临床中心代谢科的首次住院治疗。 总之，这些研究应该揭示并提供基本的见解改变基因表达的性质和释放的炎症细胞因子和其他介质的特点超重状态和动态的一系列事件发生时，饮食干预导致体重减轻。 预计这些变化中的一些将与巨噬细胞和已知的炎症标志物有关，尽管毫无疑问还有其他重要的线索有待发现。 因此，我们希望这些研究最终能够鉴定出与肥胖相关的重要代谢紊乱及其对不同治疗方式的反应相关的新基因。