Heterogeneity of Fat Depots: Biological Differences Related to Insulin Resistance

描述(申请人提供)：胰岛素抵抗(IR)是肥胖相关疾病，如糖尿病和心血管疾病的主要诱因。虽然肥胖与胰岛素抵抗有关，但这种联系的生物学基础尚不清楚，而且并不是所有肥胖的人都是胰岛素抵抗。曾经流行的门静脉假说认为，VAT的脂解作用特别是导致IR，但由于VAT只贡献了全身游离脂肪酸(FFA)总流量的15%，这一假说受到了质疑。其他提出的将肥胖与胰岛素抵抗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质量与IR的关系是否比皮下脂肪组织(SAT)质量更密切。此外，将VAT或SAT中不同的生物学活动与IR联系起来的证据是间接的，主要来自比较瘦到肥胖或VAT和SAT的研究，而不评估IR。因此，本研究的目的是探讨SAT和/或VAT促进IR的生物学机制。具体地说，我们将探索两个相关的假设-SAT中脂肪细胞分化障碍与IR、异位脂肪沉积和增值税储存库的扩张有关，以及VAT中的炎症与IR有关。利用Beckman Coulter Multisizer获得的脂肪细胞大小/分布，通过定量聚合酶链式反应进行基因表达，通过改良的胰岛素抑制试验对IR进行体内定量，以及对心肌细胞、腹内和肝内脂肪进行成像，我们的具体目的是：1)通过比较IR和择期手术受试者的细胞大小特征和分化标志物，证实SAT的脂肪细胞分化障碍与IR相关；2)检验VAT不会出现同样的关系的假设；3)证明在SAT的脂肪细胞分化受损的情况下，VAT质量扩大；4)使用细胞大小特征和分化标记物证明肌内脂肪与胰岛素抵抗和脂肪细胞分化障碍有关；5)使用炎症标记物(基因和蛋白质)证明大网膜脂肪中炎症增加与胰岛素抵抗相关，而不是肥胖。上述#1、3、4的支持性数据将来自20-23名IR患者服用16周的吡格列酮与安慰剂的对比，假设脂肪细胞分化/脂肪储存的改善，以及与胰岛素敏感性改善相关的异位和内脏脂肪的减少。与公共健康相关：肥胖率在美国和世界范围内持续上升，伴随而来的是2型糖尿病和心血管疾病的相关并发症。胰岛素抵抗(IR)与体重指数增加有关(1)，并且很可能是这些并发症的主要原因(2)。然而，并不是所有的肥胖个体都是IR(3，4)，而且有足够的数据来证明研究脂肪组织的生物学特征可以解释在特定个体中肥胖相关IR的发展：1)体重增加/减少和针对脂肪细胞的药物(噻唑烷二酮类)能够改变胰岛素敏感性(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)腹部、肝脏和骨骼肌中的脂肪沉积与IR有关(10)；4)肥胖者脂肪组织中的炎症活性高于瘦瘦者(11)，提示可能与IR有关；5)脂肪组织产生脂联素(12)等激素，可能保护个体免受IR的伤害。通过比较胰岛素抵抗和胰岛素敏感的肥胖者皮下和内脏脂肪组织的生物学特性，我们将探索皮下脂肪中脂肪细胞的分化/成熟受损和内脏脂肪中的炎症在人类肥胖背景下参与胰岛素抵抗的假设。

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.