Integrating the Metabolic and Genetic Faces of Obesity

描述（由申请人提供）：美国肥胖症患病率的快速增长代表了一个主要的健康问题。肥胖相关的心血管疾病和糖尿病风险可能与肥胖个体倾向于胰岛素抵抗和高胰岛素血症有关。然而，并非所有肥胖者都有胰岛素抵抗，在体重指数（BMI）等于或大于25.0 kg/m2的健康个体中，胰岛素介导的葡萄糖摄取（IMGU）率相差6倍以上。此外，相同性别和BMI的个体在IMGU值上存在很大差异的情况并不罕见。考虑到遗传因素可能占整个人群中IMGU变异的约50%，并且胰岛素敏感性倾向于随着体重增加而降低，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，从而导致不同的代谢后果。我们召集了一组独特的临床和基础科学家来验证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变异性的基础。具体来说，在热量过量的情况下，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个体不会产生胰岛素抵抗，而那些不能以这种方式做出反应的个体则会产生胰岛素抵抗。此外，我们假设，通过针对脂肪组织的干预，肥胖个体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，这些异常与胰岛素敏感化有关，但这些变化将不会在胰岛素敏感对照组中被观察到，而胰岛素敏感对照组在相同的干预下缺乏胰岛素敏感性的变化。因此,Drs。雷文和麦克劳克林将识别并招募年龄、性别和bmi匹配的个体，这些个体的IMGU不同。将收集脂肪组织活检，并与dr。Tsao， Cushman和Sherman，将比较脂肪细胞分化/功能的标志物，包括细胞大小分布，基因表达和胰岛素对脂肪分解的抑制。此外，将从分离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变化：减肥和噻唑二酮（TZD）治疗。我们相信，这项工作将大大填补目前关于肥胖和胰岛素抵抗之间联系的知识空白，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.