The adipocyte hormone leptin has a wide-scope of actions including regulation of weight and insulin sensitivity. We showed that leptin therapy in the setting of non-HIV lipodystrophy reverses insulin resistance, hypertriglyceridemia and nonalcoholic fatty liver disease (NAFLD). Subsequently, we have shown that 40% of male patients with nonalcoholic steatohepatitis (NASH, the most severe form of NAFLD) have relative leptin deficiency (RLD) by demonstrating a leptin level < 25th percentile of BMI- and-gender-matched NHANES III cohort. We have recently completed a pilot study that investigated effects of leptin therapy in NASH and RLD. Preliminary data are encouraging to suggest that male patients with RLD are in fact leptin-responsive as they demonstrate salutary metabolic effects as well as histopathological improvement in liver with open-label leptin therapy. We now propose to explore RLD in NASH in a broader scale. In Aim 1, we will test the efficacy of recombinant leptin therapy in 40 men with NAFLD/NASH and RLD against placebo whose diets will be controlled with moderate caloric restriction in a double-blind design for 1 year. In Aim 2, we will investigate the time course of change that we have observed over resting energy expenditure (REE). We will also explore mechanisms of change in REE by studying autonomic function, thyroid axis and brown fat mass by performing FDG- PET scanning. If this proposal is completed successfully, results may offer new clinical and molecular insights into leptin action in humans. In Aim 3, we will determine the differences in hepatic gene expression as well as serum metabolomic profiles. Preliminary data are showing interesting leads for a regulatory role for leptin in the hepatic FXR/RXR pathway. We will have the opportunity to investigate this in greater detail in a larger number of patients using a controlled diet and against placebo control.