Metabolic Markers and Predictors of Childhood Obesity

描述（由申请人提供）：青少年肥胖是美国最普遍的营养疾病。本提案寻求继续支持自1991年资助的项目，该项目专注于识别与青少年肥胖发病机制有关的早期代谢紊乱。这里提出的研究是我们以前在这一领域工作的自然延伸。本应用的重点是了解与青少年肥胖相关的胰岛素抵抗的机制。这种更新的中心假设是胰岛素抵抗和高胰岛素血症有利于体重增加，并导致青少年肥胖的相关代谢并发症。因此，针对胰岛素抵抗的干预不仅可以控制体重增加，还可以预防青少年肥胖的代谢并发症。具体目的是：1)确定与总体肥胖密切匹配的白人青少年相比，非裔美国人和西班牙裔肥胖青少年中胰岛素敏感性的种族差异是否与脂肪含量较高的细胞内（IMCL）积累有关；2)确定青少年肥胖发展过程中循环脂联素水平与胰岛素敏感性变化的纵向变化；3)确定干预措施——如使用二甲双胍（一种双胍类药物）——是否能增强胰岛素敏感性，减少高胰岛素血症，从而减少肥胖青少年的体重增加，改善心血管危险因素。结合全身代谢方法（葡萄糖钳，稳定同位素动力学和间接量热法），与新型脂肪特异性蛋白质脂联素的连续测量和1H-NMR光谱的使用，首次无创伤地评估儿童IMCL脂质储存，将提供独特的机会，以促进对儿童肥胖中胰岛素抵抗机制的理解。

DESCRIPTION (provided by applicant): Juvenile obesity is the most prevalent nutritional disease in the U.S. This proposal seeks continued support of a project funded since 1991, which focuses on the identification of early metabolic disturbances implicated in the pathogenesis of juvenile obesity. The studies proposed here are natural extensions of our previous work in this area. The focus of this application is to understand the mechanisms responsible for the insulin resistance associated with juvenile obesity. The central hypothesis of this renewal is that insulin resistance and hyperinsulinemia favor weight gain and lead to the associated metabolic complications of juvenile obesity. Thus, interventions that target insulin resistance may not only control weight gain but also prevent the metabolic complications of juvenile obesity. The specific aims are: 1) to determine whether ethnic differences in insulin sensitivity are related to greater intramyocellular (IMCL) accumulations of lipid content in obese adolescents of African American and Hispanic origin, compared to Caucasian adolescents closely matched for overall adiposity; 2) to determine longitudinal changes in circulating adiponectin levels in relation to changes in insulin sensitivity during the development of juvenile obesity; and 3) to determine whether interventions--such as the use of metformin, a biguanide--can enhance insulin sensitivity and decrease hyperinsulinemia, which will lead to a reduction in weight gain and improvement in cardiovascular risk factors in obese adolescents. The combination of whole body metabolic methods (glucose clamps, stable isotope kinetics and indirect calorimetry), together with sequential measurements of the novel adipose-specific protein adiponectin and the use of 1H-NMR spectroscopy to assess non-invasively, for the first time, IMCL lipid stores in children, will provide the unique opportunity to advance the understanding of the mechanisms underlying the insulin resistance in childhood obesity.