In some recent studies, glucocorticoid treatment was associated with rapid induction of obese (ob) gene expression in adipose tissue of normal rats and in isolated adipocytes. We studied the effect of acute stimulation of the corticotropic axis on plasma leptin, the ob gene product, in 7 women of normal weight and 12 women with obesity. Under double-blind, placebo-controlled conditions, a single 12.5-mg dose of clomipramine, a serotonin uptake inhibitor, was administered intravenously in 15 minutes. Mean basal plasma leptin was increased more than 3-fold in subjects with obesity compared with subjects of normal weight (35.1 +/- 4.9 ng/mL vs. 8.9 +/- 1.4 ng/mL, p = 0.001). Whereas corticotropin (ACTH) and cortisol responses were increased in women who were obese compared with women who were lean, no significant effect of clomipramine infusion was found on plasma leptin concentrations measured during the following 150 minutes in both groups. There was a strong positive correlation between basal plasma leptin concentrations and body mass index (r = 0.92, p < 0.0001). In six subjects with obesity studied after a moderate weight loss, mean basal plasma leptin was significantly decreased (43.7 +/- 6.4 ng/mL before vs. 28.0 +/- 8.1 ng/mL after, p = 0.04), but the hormonal response pattern to clomipramine administration was unchanged. We conclude that, at least in the short term, an acute stimulation of the corticotropic axis does not seem to increase leptin secretion in humans, as shown by the response to the serotoninergic agent clomipramine.