Heterogeneity of Fat Depots: Biological Differences Related to Insulin Resistance

脂肪库的异质性：与胰岛素抵抗相关的生物学差异

• 批准号: 7885405
• 负责人: TRACEY MCLAUGHLIN
• 金额: $ 38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-05 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885405
• 关键词: 2,4-thiazolidinedione; Abdominal Cavity; Accounting; Address; Adipocytes; Adipose tissue; Agreement; Animals; Biologic Characteristic; Biological; Body mass index; Cardiovascular Diseases; Cell Differentiation process; Cell Size; Cells; Characteristics; Conflict (Psychology); Cross-Sectional Studies; Data; Defect; Deposition; Development; Diabetes Mellitus; Differentiation Antigens; Drug Delivery Systems; Evaluation; Fatty acid glycerol esters; Gene Expression; Gene Proteins; Genes; Hepatic; Heterogeneity; Hormones; Human; IL8 gene; Image; Impairment; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interleukin-6; Intramuscular; Investigation; Laboratories; Link; Lipodystrophy; Lipolysis; Liver; Modeling; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Omentum; Operative Surgical Procedures; Patients; Peripheral; Pioglitazone; Placebos; Play; Population; Portal vein structure; Prevalence; Property; Rattus; Relative (related person); Rodent; Role; Skeletal Muscle; Testing; Thiazolidinediones; United States; Visceral; Weight Gain; Zucker Rats; adipocyte differentiation; adiponectin; bariatric surgery; base; cohort; design; glucose production; improved; in vivo; indexing; inflammatory marker; insulin sensitivity; intrahepatic; lipid biosynthesis; novel strategies; public health relevance; response; subcutaneous

DESCRIPTION (provided by applicant): Insulin resistance (IR) is a major contributor to obesity-related morbidities such as diabetes and cardiovascular disease. While obesity is associated with IR, the biological basis for this association is unclear, and not all obese individuals are IR. The once-popular portal hypothesis, which states that lipolysis from VAT in particular accounts for IR, has been questioned because VAT contributes only 15% of the total systemic free fatty acid (FFA) flux. Other proposed mechanisms linking obesity to IR include inflammation, adiponectin, and ectopic fat. It is unclear whether VAT mass is more closely linked to IR than is subcutaneous adipose tissue (SAT) mass. Furthermore, evidence linking differential biological activity to IR in VAT or SAT is indirect, largely derived from studies comparing lean to obese or VAT to SAT without evaluation of IR. Thus, the purpose of this study is to investigate the biological mechanisms by which SAT and/or VAT contribute to IR. Specifically, we will explore two related hypotheses- that impaired adipocyte differentiation in SAT is related to IR, ectopic fat deposition and expansion of VAT depot, and that inflammation in VAT is associated with IR. Utilizing adipose cell size/distribution obtained by Beckman Coulter Multisizer, gene expression via quantitative PCR, in-vivo quantification of IR via a modified insulin suppression test, and imaging of intramyocellular, intraabdominal and intrahepatic fat, our specific aims are to: 1) Confirm that impairment of adipocyte differentiation in SAT is associated with IR by comparing cell size characteristics and differentiation markers in IR and IS subjects undergoing elective surgery; 2) Test the hypothesis that the same relationship will not be seen in VAT; 3) Demonstrate that VAT mass is expanded in the presence of impaired differentiation of adipocytes in SAT; 4) Demonstrate that intramuscular fat is related to both IR and impaired differentiation of adipocytes in SAT using cell size characteristics and differentiation markers; 5) Demonstrate that increased inflammation in omental fat is associated with IR independent of obesity using inflammation markers (gene and protein). Supportive data for #1,3,4 above will be derived from pioglitazone vs placebo administration to 20-23 IR individuals for 16 weeks, with hypothesized improvement in adipose cell differentiation/fat storage and associated reduction in ectopic and visceral fat with improved insulin sensitivity. PUBLIC HEALTH RELEVANCE: The prevalence of obesity continues to rise in the United States and worldwide, bringing with it associated complications of type 2 diabetes and cardiovascular disease. Insulin resistance (IR) is associated with increasing body mass index (1), and is likely to account for the majority of these complications (2). Not all obese individuals are IR, however (3,4), and there exist sufficient data to justify investigating biological characteristics of adipose tissue that might explain the development of obesity- associated IR in select individuals: 1) weight gain/loss and drugs targeting fat cells (thiazolidinediones) have the ability to alter insulin sensitivity (5,6); 2) lipodystrophy models in humans and animals are associated with altered deposition of fat and IR (7-9); 3) fat deposition in the abdominal cavity, liver, and skeletal muscle is associated with IR (10); 4) inflammatory activity in adipose tissue is higher in obese vs lean individuals (11), suggesting a possible link with IR; 5) adipose tissue produces hormones such as adiponectin (12), that may protect individuals from IR. By comparing biological properties of subcutaneous and visceral adipose tissue from obese individuals who are IR vs insulin sensitive, we will explore the hypothesis that impaired differentiation/maturation of adipose cells in subcutaneous fat, and inflammation in visceral fat contributes to IR in the setting of human obesity.

描述（由申请人提供）：胰岛素抵抗（IR）是导致与肥胖相关的病因（例如糖尿病和心血管疾病）的主要因素。尽管肥胖与IR相关，但这种关联的生物学基础尚不清楚，并且并非所有肥胖个体都是IR。曾经受欢迎的门户假设指出，尤其是IR的脂肪分解，因为增值税仅占全身游离脂肪酸（FFA）通量的15％，因此受到了质疑。将肥胖与IR联系起来的其他提出的机制包括炎症，脂联素和异位脂肪。目前尚不清楚大桶质量是否与皮下脂肪组织（SAT）质量更紧密地联系在一起。此外，将差异性生物活性与增值税或SAT中的IR联系起来的证据是间接的，主要来自于将瘦肉，肥胖或增值税与IR评估的研究相比，将瘦肉与肥胖或增值税与SAT进行比较。因此，这项研究的目的是研究SAT和/或增值税对IR的生物学机制。具体而言，我们将探讨两个相关的假设 - SAT中脂肪细胞分化受损与IR，异位脂肪沉积和增值税仓库的扩张有关，并且VAT中的炎症与IR有关。利用通过贝克曼·库尔特多渗透剂获得的脂肪细胞的大小/分布，通过定量PCR来表达基因表达，通过改进的胰岛素抑制测试对IR进行体内定量，以及对腹腔内，腹腔内和ePHEPHEP的成像进行成像，我们的特定目的是与IR的尺寸相关的IR与ADIPCIAR的不同相关性：1）与IR相关性。并且是接受选修手术的受试者； 2）检验以下假设：在增值税中不会看到相同的关系； 3）证明，在SAT中脂肪细胞分化受损的情况下，增值税质量扩大； 4）证明肌内脂肪与使用细胞大小特征和分化标记物在SAT中的IR和SAT中的分化受损有关。 5）证明，使用炎症标志物（基因和蛋白质）与肥胖无关的IR炎症增加与IR有关。上述＃1,3,4的支持数据将从吡格列酮与安慰剂给药到20-23个个体16周中得出，并提高了脂肪细胞分化/脂肪储存/脂肪储存，以及相关的异位和内脏脂肪的减少，并改善了胰岛素敏感性。公共卫生相关性：在美国和世界范围内，肥胖症的流行率不断增加，这与2型糖尿病和心血管疾病的并发症相关。胰岛素抵抗（IR）与体重指数的增加有关（1），并且可能解释了这些并发症的大多数（2）。但是，并非所有肥胖个体都是IR，但是（3,4），并且存在足够的数据来证明研究脂肪组织的生物学特征是合理的，这可能解释了某些个体中肥胖与IR的发展：1）靶向脂肪细胞的体重/损失和靶向脂肪细胞（噻唑烷固醇）的药物具有改变胰岛素敏感性的能力（5,6）； 2）人类和动物的脂肪营养不良模型与脂肪和IR的沉积改变有关（7-9）； 3）腹腔，肝脏和骨骼肌中的脂肪沉积与IR（10）有关； 4）肥胖个体与瘦肉个体的脂肪组织中的炎症活性更高（11），这表明可能与IR有联系； 5）脂肪组织会产生激素，例如脂联素（12），可以保护个体免受IR的侵害。通过比较来自IR与胰岛素敏感的肥胖个体的皮下和内脏脂肪组织的生物学特性，我们将探讨以下假设：皮下脂肪中脂肪细胞的分化/成熟/成熟，以及在人类肥胖症的情况下，炎症中的脂肪细胞的分化/成熟和炎性脂肪对IR有影响。