The long-term goal of this research program is to understand the underlying mechanism of obesity, including both diet-induced and age-related obesity. Increased body weight is an important public health problem because it is associated with type II diabetes, hypertension and hyperlipidemia. Current research is focused on the mechanism of action of leptin and the role of leptin resistance in obesity. Leptin, synthesized by white adipose tissue (WAT), is an afferent signal molecule that interacts with the appetite and satiety centers in the brain to regulate body weight, and this hormone contributes to the regulation of both food intake and energy expenditure. Our approach uses both pharmacological and gene delivery techniques. We are investigating the mechanism of action of leptin in young-lean animal compared with diet-induced obese rats and compared to aged-obese rats. Studies focus on leptin signal transduction in the hypothalamus and identifying downstream components of the leptin signal transduction cascade both in the brain and in peripheral tissues. In addition, we are examining the site of leptin resistance with age or obesity by sequentially stimulating downstream elements of the leptin signal transduction cascade. Lastly, we are attempting to reverse or prevent the development of obesity with diet or age with gene delivery techniques aimed at both circumventing the leptin resistance and independently activating energy expenditure mechanisms.