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）是导致糖尿病和心血管疾病等肥胖相关疾病的主要原因。虽然肥胖与 IR 相关，但这种关联的生物学基础尚不清楚，而且并非所有肥胖个体都是 IR。曾经流行的门户假说指出，增值税的脂肪分解尤其是 IR 的原因，但这一假说受到了质疑，因为增值税仅占全身游离脂肪酸 (FFA) 通量的 15%。其他提出的将肥胖与IR联系起来的机制包括炎症、脂联素和异位脂肪。目前尚不清楚 VAT 质量是否比皮下脂肪组织 (SAT) 质量与 IR 的关系更密切。此外，将差异生物活性与 VAT 或 SAT 中的 IR 联系起来的证据是间接的，主要来自比较瘦与肥胖或 VAT 与 SAT 的研究，而没有评估 IR。因此，本研究的目的是调查 SAT 和/或 VAT 促进 IR 的生物学机制。具体来说，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 VAT 库扩张有关，以及 VAT 中的炎症与 IR 相关。利用 Beckman Coulter Multisizer 获得的脂肪细胞大小/分布、通过定量 PCR 进行的基因表达、通过改进的胰岛素抑制试验对 IR 进行体内定量，以及肌细胞内、腹腔内和肝内脂肪的成像，我们的具体目标是： 1) 确认通过比较接受择期手术的 IR 和 IS 受试者的细胞大小特征和分化标记物，发现 SAT 中脂肪细胞分化受损与 IR 相关； 2）检验VAT中不会出现相同关系的假设； 3）证明在SAT中脂肪细胞分化受损的情况下VAT质量会扩大； 4) 使用细胞大小特征和分化标记证明肌内脂肪与 IR 和 SAT 中脂肪细胞分化受损有关； 5) 使用炎症标志物（基因和蛋白质）证明网膜脂肪炎症增加与 IR 相关，与肥胖无关。上述 #1、3、4 的支持性数据将来自对 20-23 名 IR 个体服用吡格列酮与安慰剂 16 周的比较，假设脂肪细胞分化/脂肪储存得到改善，异位脂肪和内脏脂肪减少，胰岛素敏感性提高。公共卫生相关性：在美国和世界范围内，肥胖症的患病率持续上升，并带来了 2 型糖尿病和心血管疾病的相关并发症。胰岛素抵抗 (IR) 与体重指数增加相关 (1)，并且可能是这些并发症的大部分原因 (2)。然而，并非所有肥胖个体都是 IR (3,4)，并且有足够的数据证明研究脂肪组织的生物学特征是合理的，这可能解释某些个体中与肥胖相关的 IR 的发展：1) 体重增加/减少和靶向药物脂肪细胞（噻唑烷二酮类）能够改变胰岛素敏感性 (5,6)； 2) 人类和动物脂肪营养不良模型与脂肪和 IR 沉积的改变有关 (7-9)； 3）腹腔、肝脏和骨骼肌中的脂肪沉积与IR相关（10）； 4) 与瘦人相比，肥胖者的脂肪组织炎症活动更高 (11)，这表明可能与 IR 有关； 5) 脂肪组织产生脂联素 (12) 等激素，可以保护个体免受 IR 的侵害。通过比较对 IR 和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/成熟受损，以及内脏脂肪中的炎症在人类环境中导致 IR。肥胖。