Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Serum leptin concentrations increase in correlation with the percentage of body fat, but besides that little is known about the physiological actions of leptin in humans. The aim of this study was to assess the influence of changes in circulating free-fatty acids on serum leptin levels. Increases in plasma FFA levels (p < 0.02) were obtained in a group of normal subjects following the administration of intralipid plus heparin (250 ml 10% Intralipid plus 5000 U heparin). FFA reduction was achieved through the administration of acipimox (250 mg, orally, at 0 min and at 210 min), a lipid-lowering drug devoid of side effects, to a group of normal (p < 0.02) and obese subjects (p < 0.05). An increase in circulating FFA levels in normal subjects (n = 6), following administration of a lipid-heparin infusion, failed to modify plasma leptin levels as assessed by the area under the curve (AUC; mean +/- SE 892 +/- 168 for placebo vs 896 +/- 260 following intralipid plus heparin). Similarly, whereas acipimox pretreatment induced a reduction in FFA levels compared to placebo in normal (n = 6) and obese subjects (n = 8), it also failed to modify plasma leptin levels at any time-point studied. The results indicate that short-term reduction or increase in circulating FFA are not associated to changes in plasma leptin levels.