BACKGROUND:Leptin, a circulating hormone secreted from adipocytes, is an index of adiposity and is reduced by caloric restriction and weight loss. A recent population study suggested that dietary-derived omega3 fatty acids lower leptin levels independent of body fat. OBJECTIVE:To examine whether dietary fish enhanced the effects of weight loss on serum leptin levels, in 69 overweight, treated hypertensive men and women. METHODS:Participants were randomized to a daily fish meal, a weight-reduction regimen, the two regimens combined or a control group for 16 weeks. RESULTS:A total of 63 individuals completed the study. Weight fell 5.6 +/- 0.8 kg with energy-restriction. Blood pressure (BP) reductions in the combined fish-weight loss group were twice that seen with either intervention alone. At baseline, in all groups combined, serum leptin levels correlated with serum insulin (r = 0.307, P = 0.014), but not with body weight. The greatest change in serum leptin occurred in the fish-weight loss group (control, 0.60 +/- 0.76 ng/ml; fish, 1.20 +/- 0.79 ng/ml; weight loss, -1.40 +/- 1.05 ng/ml; fish-weight loss, -5.08 +/- 1.64 ng/ml). In the fish-weight loss group, the change in serum leptin was predicted by changes in serum insulin (r = 0.488, P = 0.038), 24-h BP (systolic BP (SBP): r = 0.435, P = 0.060; diastolic BP (DBP): r = 0.563, P = 0.018) and 24-h heart rate (0.584, P = 0.028). Using general linear models, there was a significant fish x weight-loss interaction (P = 0.008) on post-intervention serum leptin after adjustment for baseline levels, independent of post-intervention insulin. CONCLUSION:A daily fish meal as part of a weight-reducing regimen was more effective than either measure alone at reducing leptin levels. Reductions in leptin may be related to the substantial fall in BP seen with the fish-weight loss program.