Leptin, a hormone secreted by the adipocytes, plays a central role in glucose metabolism and the action of insulin. Here we assessed, by means of rat-liver perfusion, the direct influence of physiological (10 ng/ml) and supraphysiological (50 or 100 ng/ml) concentrations of leptin on the suppressive effect of insulin on the glucose production and glycogenolysis stimulated by 8-bromoadenosine-3':5'-monophosphate (8-Br-cAMP). Portal infusion of insulin (20 microU/ml) or leptin (10 ng/ml) reduced (p<0.05) the glucose production and glycogenolysis induced by 8-Br-cAMP (0.3 microM). However, portal infusion of physiological (10 ng/ml) and supraphysiological (50 or 100 ng/ml) concentrations of leptin together with the insulin did not modify the suppressive effect of the latter on the glucose production and glycogenolysis stimulated by 8-Br-cAMP. Moreover, prolonging the period of leptin infusion from 20 to 40 min also failed to influence the liver response to insulin. Thus, we conclude that: (a) leptin, at physiological levels, has a direct and acute effect, inhibiting the glucose production and glycogenolysis stimulated by 8-Br-cAMP; (b) leptin, at either physiological or supraphysiological concentrations, has no short-term influence on the suppressive effect of insulin on glycogen catabolism stimulated by 8-Br-cAMP.