? Obesity and insulin resistance afflict millions of Americans. Among emerging co-morbidities of obesity and insulin resistance, is a condition called nonalcoholic fatty liver disease (NAFLD). A more aggressive form of NAFLD is called nonalcoholic steatohepatitis (NASH), characterized by the presence of steatosis, inflammation and varying degrees of scarring. NASH can progress into cirrhosis and permanent liver failure. Using data and estimations to be presented within the body of the application, there are at least 5 million people in the US with NASH. Thus, discovery of effective strategies to treat NASH will make a big impact on health-care costs in the US. The adipocyte-hormone leptin is thought to play a role in modulating lipid deposition in the liver, the first step of fatty liver disease. Treatment with leptin in rodent leptin deficiency ameliorates fatty deposition in the liver. Studies in human lipodystrophy and leptin deficiency indicate that correction of leptin deficiency results in amelioration of cellular injury in addition to reversing steatosis. These observations warrant the investigation of leptin's role in NASH. We have previously determined serum leptin levels of patients with known fatty liver disease and observed that approximately 20% of patients with NASH and up to 40% of male patients with NASH demonstrate relative leptin deficiency, making them ideal candidates for restorative therapy with recombinant leptin. For this study, we will screen serum leptin levels of non-diabetic male patients with BMI<40kg/m2 who are identified as having biopsy proven NASH. Among those, we will enroll 10 subjects who are relatively leptin deficient (levels<25th percentile of NHANES III levels for their BMI and gender) for a therapeutic trial with recombinant human leptin (Amgen, Thousand Oaks, California) which will be administered subcutaneously at a dose of 0.1 mg/kg/day for 1 year. Liver histopathology at the end of 1 year will be the primary outcome of the study. Parameters of body composition and metabolic state will also be monitored. We will also investigate the potential mechanisms involved in leptin's action. Approximately 1 million Americans may derive direct benefit from the implications of this research application, since we are targeting approximately 20% of patients with NASH. ? ?