The aim of the study was to investigate the effects of energy restriction with or without pegylated recombinant leptin (PEG-leptin) treatment on ghrelin, adiponectin, insulin and glucose concentrations. A randomized double-blind placebo-controlled trial was performed in 24 moderately overweight/obese men. PEG-leptin or placebo was administered weekly for 6 weeks, combined with a restricted energy intake of 2.1 MJ/d. At days 1, 25, and 46 a blood sample was taken and body-weight (BW) was measured. Days 1-25 was named phase 1, and days 25-46 phase 2. During phase 1 the rate of BW loss was significantly higher in the PEG-leptin compared to the placebo group (0.38+/-0.07 vs 0.32+/-0.06 kg/d, p<0.05). The rate of BW loss during phase 2 was 0.24+/-0.08 and 0.18+/-0.09 kg/d, respectively (p=0.07). In both groups the rate of BW loss during phase 1 was significantly higher than during phase 2 (p<0.001). Energy balance (EB) was significantly more negative during phase 1 than during phase 2 in both groups (p<0.0005). During phase 1 insulin, glucose and adiponectin decreased significantly in both groups. Adiponectin and ghrelin concentrations changed in the opposite direction between phase 1 and phase 2 (p<0.05). Initial BW loss due to a considerable negative EB induced decreased ghrelin, adiponectin, insulin and glucose levels. However, when EB became less negative and the rate of BW loss decreased, these changes were reversed for adiponectin and ghrelin. The PEG-leptin injections did not have an effect on the changes in insulin, glucose and adiponectin, but had an effect on the changes in ghrelin concentrations. AD - Department of Human Biology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.