Integrating the Metabolic and Genetic Faces of Obesity

描述(由申请者提供)：美国肥胖症患病率的迅速上升代表着一个主要的健康问题。与肥胖相关的心血管疾病和糖尿病的风险可能与肥胖个体往往是胰岛素抵抗和高胰岛素血症有关。然而，并不是所有的肥胖者都有胰岛素抵抗，体重指数(BMI)等于或超过25.0公斤/平方米的健康人的胰岛素介导的葡萄糖摄取率(IMGU)差异超过6倍。此外，相同性别和体重指数的个体对IMGU的价值观差异很大，这并不少见。考虑到遗传因素可能解释了一般人群IMGU变异性的大约50%，而且胰岛素敏感性随着体重的增加而降低，似乎很明显，差异基因表达影响脂肪细胞对热量过剩/肥胖的反应方式，导致不同的代谢后果。我们已经召集了一个独特的临床和基础科学家小组来测试这一假设，即与脂肪细胞分化和功能相关的差异基因表达是与肥胖相关的IMGU变异的基础。具体地说，在卡路里过量的情况下，能够增加脂肪生成、增加脂肪组织中FFA的摄取和储存、增加抗炎和减少炎症性脂肪细胞因子分泌的人不会出现胰岛素抵抗，而不能以这种方式做出反应的人将是胰岛素抵抗。此外，我们假设，肥胖个体中的胰岛素抵抗亚组将表现出脂肪细胞分化和终末功能的异常，这些异常与针对脂肪组织的胰岛素敏化相关，但在同样干预下胰岛素敏感性缺乏变化的胰岛素敏感组中不会看到这些变化。因此，Reaven博士和McLaughlin博士将识别和招募年龄、性别和BMI匹配的IMGU不同的人。将采集脂肪组织活检组织，并与曹博士、库什曼博士和谢尔曼博士合作，比较脂肪细胞分化/功能的标志，包括细胞大小分布、基因表达和脂肪分解的胰岛素抑制。此外，将从分离的血浆中测量脂肪细胞因子的产生。最后，我们将评估两种针对脂肪组织的胰岛素增敏干预措施的这些标志物的变化：减肥和噻唑二酮(TZD)治疗。我们相信，这项工作将大大增加目前关于肥胖和胰岛素抵抗之间联系的知识差距，并最终有助于开发新的治疗靶点。

DESCRIPTION (provided by applicant): The rapid increase in the prevalence of obesity in the US represents a major health problem. Obesity-associated risks of cardiovascular disease and diabetes mellitus are likely related to the fact that obese individuals tend to be insulin resistant and hyperinsulinemic. Not all obese individuals are insulin resistant, however, and insulin-mediated glucose uptake (IMGU) rates vary more than six-fold in healthy individuals whose body mass index (BMI) is equal to or more than 25.0 kg/m2. Furthermore, it is not uncommon for individuals of the same gender and BMI to have widely divergent values for IMGU. Given that inherited factors are likely to account for approximately 50% of the variability in IMGU in the population at large, and that insulin sensitivity tends to decrease as body weight increases, it seems evident that differential gene expression influences the manner in which adipocytes respond to caloric excess/obesity, leading to different metabolic consequences. We have assembled a unique group of clinical and basic scientists to test the hypothesis that differential gene expression related to adipocyte differentiation and function underlies the variability in IMGU associated with obesity. Specifically, individuals who, in the setting of caloric excess, are able to increase adipogenesis, increase FFA uptake and storage in adipose tissue, and increase anti-inflammatory and decrease inflammatory adipocytokine secretion, will not be insulin resistant, while those who are not able to respond in this manner will be insulin-resistant. Furthermore, we hypothesize that the insulin-resistant subgroup of obese individuals will demonstrate abnormalities in adipocyte differentiation and terminal function that improve in association with insulin sensitization via interventions targeting adipose tissue, but that these changes will not be seen in insulin-sensitive controls that lack change in insulin sensitivity with the same interventions. Thus, Drs. Reaven and McLaughlin will identify and recruit age-, sex- and BMI-matched individuals who differ in their IMGU. Adipose tissue biopsies will be harvested and, in collaboration with Drs. Tsao, Cushman and Sherman, markers of adipocyte differentiation/function will be compared including cell size distribution, gene expression, and insulin-suppression of lipolysis. In addition, adipocytokine production will be measured from isolated plasma. Finally, we will evaluate changes in these markers to two insulin-sensitizing interventions that target adipose tissue: weight loss and thiazolidenedione (TZD) treatment. We believe that this work will add substantially to the current gap in knowledge regarding the link between obesity and insulin-resistance, and ultimately aid in the development of novel therapeutic targets.