Obesity has reached epidemic proportions, affecting 30% of Americans, with a projected prevalence of 50% by 2030. The increasing prevalence of obesity has been associated with adverse health outcomes including diabetes, cardiovascular disease and cancer. Despite successful weight loss that could, if sustained, improve risk of negative health outcomes, the majority of weight reduced persons return to baseline body weight over a period of time following successful dietary and pharmacotherapy intervention. The mechanisms responsible for this return to baseline bodyweight remain unknown. Leptin is a protein secreted by adipocytes which acts to reduce appetite and increase energy expenditure. Leptin levels are increased in proportion to the degree of adiposity and circulating leptin levels decrease with weight loss. Our group has shown that decreasing leptin levels mediate the neuroendocrine response to food deprivation in both animals and humans. Thus, reduced leptin levels associated with weight loss could be responsible for defending baseline body weight by reducing thyroid hormone levels, reducing sympathetic nervous system activity and reducing metabolic rate. Although we have demonstrated that leptin regulates neuroendocrine function in lean subjects, the above hypothesis has never been studied in the setting of a randomized, controlled trial involving obese subjects who are apparently tolerant or resistant to leptin. Also, although animal studies indicate that leptin sensitivity is associated with changes in the expression of leptin receptor and second messengers of leptin signaling in leptin sensitive tissues, any changes that occur in these proteins with weight loss have never been studied in humans. We propose to study the role of leptin in defending baseline body weight by performing a placebo-controlled, randomized study of leptin administration to weight reduced obese subjects. By careful study of body weight, body composition, neuroendocrine function and metabolic rate, we plan to study the mechanisms involved in return to baseline body weight and the effect of leptin administration in preventing this. We also plan to study the changes in leptin signaling and leptin receptor expression. This novel and clinically relevant role for leptin is an area that urgently requires further study. Understanding the biology of the defense against weight loss will help to plan appropriate long-term weight maintenance therapies and ensure that obese patients derive long-term benefit from their efforts to reduce weight. PUBLIC HEALTH RELEVANCE: Obesity has reached epidemic proportions, affecting 30% of Americans, with a projected prevalence of 50% by 2030. Several effective therapies, including lifestyle interventions, are available however the majority of individuals who manage to lose a clinically significant amount of weight, generally regain that weight over a period of months and years. Understanding the mechanisms and developing effective therapies to combat this phenomenon is of huge public health importance.