Compelling evidence indicates that leptin, acting via specific receptors (Ob-Ra and Ob-Rb) modulates adrenocortical-cell secretion. However, the results are controversial, inasmuch as either secretagogue or antisecretagogue effects have been reported. Hence, we decided to study the effects of a 96-h incubation with leptin and leptin fragments 116-130, 150-167, 138-167, 93-105, 22-56 and 26-39 (10(-8) and 10(-6) M) on the secretion and growth of cultured rat adrenocortical cells. Reverse transcription-polymerase chain reaction showed that control cultures expressed both Ob-Ra and Ob-Rb isoforms. As expected, ACTH (10(-8) M) raised corticosterone secretion and lowered proliferation rate of cultured cells. Native leptin elicited ACTH-like effects, while fragment 116-130 was ineffective. Leptin fragments 150-167 and 26-39 stimulated corticosterone production, and fragments 138-167 and 22-56 inhibited it. Fragment 93-105 exerted a dose-dependent biphasic effect on corticosterone secretion (i.e. stimulation and inhibition at the concentration of 10(-8) and 10(-6) M, respectively). Leptin fragment 26-39 enhanced proliferation of cultured cells, while fragments 138-167 and 22-56 were ineffective. Fragments 150-167 and 93-105 displayed proliferogenic and antiproliferogenic effects at the concentration of 10(-8) and 10(-6) M, respectively. Taken together, these findings allows us to conclude that native leptin and its fragments interact differently with Ob-Rs or interact with different Ob-R isoforms, thereby variously modulating secretion and growth of cultured rat adrenocortical cells.