This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalence of overweight in childhood, defined by age specific body mass index (BMI) >95% percentile, has tripled in the United States in the last 30 years. Overweight asolescents are at greater risk for non-alcoholic fatty liver disease (NAFLD). However, the natural history of NAFLD in children in not known. All published studies evaluating this issue have been retrospective cross sectional analysis or retrospecitve analyses of selected patients that had multiple liver biopsies. The metabolic abnormalities associated with NAFLD and the appropriate therapeutic approach for overweight adolescents with NAFLD are not known. NAFLD represents a spectrum of liver diseases that can be characterized histologically as steatosis, steatohepatitis, fibrosis and cirrhosis. However, the mechanism(s) responsible for developing NAFLD in overweight adolescents and the effects of NAFLD itself on metabolic function are not known. This gap in our basic understanding of this disease has made it difficult to identify effective treatments, and the appropriate therapeutic approach to NAFLD is not known. Although weight loss is generally recommended for obese patients with NAFLD, the available data suggest that rapid and marked weight loss increases inflammation, and even liver failure. Therefore, the primary goal is this proposal is to provide a better understanding of: 1) the pathogenesis and pathophysiology of NAFLD in overweight adolescents, and 2) the effect of maked weight loss on the histologic and metabolic abnormalities associated with NAFLD. These studies will lay the groundwork for the development of new therapeutic interventions for overweight adolescents with NAFLD. The major purpose of this study is to test the hypothesis that: 1) NAFLD in overweight adolescents is associated with insulin resistance in liver, skeletal muscle and adipose tissue, and altered hepatic lipoprotein metabolism, and 2) weight loss improves the metabolic abnormalities associated with NAFLD.
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