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.
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