Obesity and Inflammation

肥胖和炎症

基本信息

项目摘要

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(s) 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 mediators, cytokines (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 and we continue to enroll patients in the protocol. At present, 30 Normal Weight and 70 Overweight study volunteers have successfully completed their first inpatient admissions (Baseline) to the Metabolic Unit of the Clinical Center. 63 Overweight subjects have been studied at 1.5 months, 56 at 3 months, 44 at 6 months, 35 at 9 months, and 33 at 12 months following the institution of the dietary intervention and nutritional counseling. The patients have been extraordinarily successful in losing weight, the average rate of weight loss being 0.5 lbs/week or 25 lbs/year (total weight loss for the group = 740 lbs). Identification and quantitation of adipokines, cytokines, and lipid mediators of inflammation in microdialysis fluids and serum have begun and results are being analyzed. The data indicate that different patterns exist for cytokines in relation to microdialysis fluid as compared to serum and that profound changes in levels of lipid mediators occur with weight loss, several of which correlate with improvements in insulin resistance. 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。 人类的数据相当缺乏,当前文献中只有少数关于该主题的文章。 在这个临床方案中,我们建议通过使用标准微阵列技术对来自活检的皮下脂肪组织样本进行测试和重新确认超重受试者中特定基因集被激活(或失活)的想法,来扩展人类的早期和不断发展的工作。 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,TNF-α、IL-6)和类花生酸(如前列腺素E2、脂氧素A4和白三烯B4)将使用灵敏的液相色谱-串联质谱法和ELISA方法进行分析。 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,我们将继续在方案中招募患者。 目前,30名正常体重和70名超重研究志愿者已成功完成临床中心代谢科的首次住院(基线)。 63名超重受试者在饮食干预和营养咨询机构后1.5个月、56名在3个月、44名在6个月、35名在9个月和33名在12个月进行了研究。 患者在减肥方面非常成功,平均减肥率为0.5磅/周或25磅/年(该组的总体重减轻= 740磅)。 微透析液和血清中脂肪因子、细胞因子和炎症脂质介质的鉴定和定量已经开始,结果正在分析中。 数据表明,与血清相比,微透析液中细胞因子存在不同的模式,并且随着体重减轻,脂质介质水平发生深刻变化,其中一些与胰岛素抵抗的改善相关。 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。

项目成果

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Louis Simchowitz其他文献

Louis Simchowitz的其他文献

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{{ truncateString('Louis Simchowitz', 18)}}的其他基金

Obesity and Inflammation
肥胖和炎症
  • 批准号:
    8349785
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
Obesity and Inflammation
肥胖和炎症
  • 批准号:
    7734148
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
Obesity and Inflammation
肥胖和炎症
  • 批准号:
    7593617
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
Obesity and Inflammation
肥胖和炎症
  • 批准号:
    7967467
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
NIDDK Office of Fellow Recruitment and Career Development
NIDDK 研究员招募和职业发展办公室
  • 批准号:
    8554235
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
NIDDK Office of Fellow Recruitment and Career Development
NIDDK 研究员招募和职业发展办公室
  • 批准号:
    7970449
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
NIDDK Office of Fellow Recruitment and Career Development
NIDDK 研究员招募和职业发展办公室
  • 批准号:
    8149753
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
Obesity and Inflammation
肥胖和炎症
  • 批准号:
    8148792
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
NIDDK Office of Fellow Recruitment and Career Development
NIDDK 研究员招募和职业发展办公室
  • 批准号:
    8350248
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:
NIDDK Office of Fellow Recruitment and Career Development
NIDDK 研究员招募和职业发展办公室
  • 批准号:
    7734286
  • 财政年份:
  • 资助金额:
    $ 16.73万
  • 项目类别:

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Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
  • 批准号:
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    26450168
  • 财政年份:
    2014
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    Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
  • 批准号:
    257256526
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增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
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  • 财政年份:
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增强白色脂肪组织中的能量消耗脂肪细胞
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    8520690
  • 财政年份:
    2013
  • 资助金额:
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Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8629741
  • 财政年份:
    2013
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Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
  • 批准号:
    23700778
  • 财政年份:
    2011
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    $ 16.73万
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    Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
  • 批准号:
    21780261
  • 财政年份:
    2009
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LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
  • 批准号:
    7610781
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