Study Overview This study is a randomized, double-blind, placebo-controlled study of leptin administration to individuals with a recent 10% weight loss, achieved through lifestyle intervention program. In this study proposal, we propose that 90 subjects who have recently completed a lifestyle intervention weight loss program (at one of the four participating Boston Weight loss centers) and have achieved a weight loss of more than 10% body weight will be enrolled in the study. They will have baseline studies performed (including full neuroendocrine evaluation as described below) and will be randomized to leptin/placebo in the ratio 1:1 after stratification by center. They will continue to receive standard weight maintenance advice with intermittent nutrition and behavioral counseling. Our aim is to finally study a total of 36 subjects per treatment arm (20% drop out or inability to achieve and/or maintain10% weight loss expected). Leptin levels will be checked every month and the dose will be titrated to achieve and keep serum levels equivalent to those at baseline based on baseline weight. We will start the leptin/placebo at a dose of 0.08mg/kg fat mass in men and 0.14mg/kg fat mass in women, with dose titration to achieve baseline leptin levels utilizing formulas derived from our pharmacokinetic studies Leptin levels will be checked every month. Circulating leptin levels between +30% and -10% of baseline will be considered acceptable. Otherwise, the leptin dose will be adjusted accordingly. Our aim is to keep the mean leptin level at or within +30% of baseline. Subjects will be studied prior to receiving leptin, after four weeks and six months of weight maintenance and we will compare changes in body weight and composition, neuroendocrine function, and metabolic function between the leptin and placebo-treated groups. In addition, the first 23 subjects per group will have measurement of total energy expenditure performed using doubly labeled water at baseline and 6 months. This will allow us to examine the effects of leptin replacement, to levels observed at baseline body weight, on the maintenance of weight loss and the neuroendocrine and metabolic adaptation to decreasing body weight in obese individuals. While difference in weight maintenance at six months will be our primary outcome, subjects will also be studied after 4 weeks of weight maintenance, which will allow us to determine the role of leptin in the adaptation to weight loss under stable, weight maintenance conditions. We have chosen the four week time point as previous nonrandomized, uncontrolled studies have been able to document an effect of leptin replacement after this time. Both groups will be followed for an extended 6-month period during which they will receive standard weight maintenance advice, in addition to leptin/placebo. We will observe the changes in weight, neuroendocrine function, metabolic function and leptin signaling over this time and compare the leptin and placebo groups. In this subset of 23 subjects per group we will evaluate energy expenditure by doubly labeled water. Finally, subjects will be followed for a further 6 months after the end of the study to document further changes in body weight as an additional study outcome.