Metabolic Markers and Predictors of Childhood Obesity

描述（由申请人提供）：青少年肥胖症是美国最普遍的营养性疾病。该提案寻求自1991年以来资助的一个项目的持续支持，该项目侧重于识别与青少年肥胖症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的工作的自然延伸。本申请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，并导致相关的代谢并发症的青少年肥胖。因此，针对胰岛素抵抗的干预措施不仅可以控制体重增加，还可以预防青少年肥胖症的代谢并发症。具体目标是：1）确定胰岛素敏感性的种族差异是否与非裔美国人和西班牙裔的肥胖青少年中脂质含量的更大的肌内（IMCL）积累相关，与整体肥胖密切匹配的高加索青少年相比; 2）确定在青少年肥胖发展期间与胰岛素敏感性变化相关的循环脂联素水平的纵向变化;以及3）确定干预措施--例如使用二甲双胍（一种双胍）--是否可以增强胰岛素敏感性和降低高胰岛素血症，这将导致肥胖青少年体重增加减少和心血管危险因素改善。全身代谢方法（葡萄糖钳、稳定同位素动力学和间接量热法）的结合，以及新型脂肪特异性蛋白脂联素的连续测量，并使用1H-NMR光谱法首次无创评估IMCL儿童体内的脂质储存，将提供独特的机会来促进对儿童肥胖胰岛素抵抗机制的了解。

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.