Heterogeneity of Fat Depots: Biological Differences Related to Insulin Resistance

描述（由申请人提供）：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，并且并非所有肥胖个体都是IR。曾经流行的门户假说（其指出特别是来自VAT的脂解导致IR）受到质疑，因为VAT仅占全身游离脂肪酸（FFA）流量的15%。其他提出的肥胖与IR相关的机制包括炎症、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更密切相关。此外，在VAT或SAT中，将差异生物活性与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导致IR的生物学机制。具体而言，我们将探讨两个相关假设-SAT中受损的脂肪细胞分化与IR相关，利用Beckman Coulter Multisizer获得的脂肪细胞大小/分布，通过定量PCR进行基因表达，通过改良的胰岛素抑制试验进行IR的体内定量，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）通过比较经历选择性手术的IR和IS受试者中的细胞大小特征和分化标志物，确认SAT中脂肪细胞分化的受损与IR相关; 2）测试在VAT中不会看到相同关系的假设; 3）证明在SAT中脂肪细胞分化受损的情况下VAT质量扩大; 4）使用细胞大小特征和分化标志物证明肌内脂肪与IR和SAT中脂肪细胞分化受损两者相关; 5）使用炎症标志物（基因和蛋白质）证明网膜脂肪中增加的炎症与IR相关，而与肥胖无关。上述#1、3、4的支持性数据将来自20-23名IR个体接受吡格列酮与安慰剂给药16周，假设脂肪细胞分化/脂肪储存改善，异位和内脏脂肪减少，胰岛素敏感性改善。公共卫生相关性：肥胖症的患病率在美国和世界范围内持续上升，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）与体重指数增加有关（1），并且可能是这些并发症的主要原因（2）。然而，并非所有的肥胖个体都是IR（3，4），并且存在足够的数据来证明调查脂肪组织的生物学特征是合理的，这些生物学特征可以解释在选择的个体中肥胖相关IR的发展：1）体重增加/减轻和靶向脂肪细胞的药物（噻唑烷二酮类）具有改变胰岛素敏感性的能力（5，6）; 2）人和动物的脂肪代谢障碍模型与脂肪沉积和IR的改变有关（7-9）; 3）腹腔、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个体（11），表明可能与IR有关; 5）脂肪组织产生激素如脂联素（12），其可以保护个体免受IR。通过比较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导致人肥胖背景下IR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.