Leptin circulates in blood and is involved in body weight control primarily via hypothalamic receptors. To examine its direct metabolic action, effects of short-term portal leptin infusion: 1) on postprandial basal and epinephrine-stimulated glycogenolysis; and 2) on postabsorptive lactate-stimulated gluconeogenesis were studied in isolated perfused rat livers. Incremental epinephrine (150 pmol x min-1 x g-1 liver)-stimulated glucose release (in micromol/g liver within 30 minutes; control: 28.3 +/- 2.8) was suppressed (P <.05) by 44% (15.8 +/- 1.6), by 48% (14.6 +/- 4.1), and by 53% (13.3 +/- 2.1) during insulin (3 pmol x min-1 x g-1 liver), leptin (30 pmol x min-1 x g-1 liver), and simultaneous leptin + insulin infusion. Perfusate cyclic adenosine monophosphate increased approximately twofold during epinephrine stimulation in all groups. Neither leptin nor insulin affected hepatic lactate production, bile flow, or portal pressure in the fed state. In the postabsorptive state (20-hour fasting), rates of lactate (10 mmol/L)-dependent hepatic glucose release (in micromol. min-1 x g-1 liver; control: 0.12 +/- 0.01) were increased (P <.01) to 0.35 +/- 0.02 and to 0.24 +/- 0.01 by glucagon (3 pmol x min-1 x g-1 liver) and by leptin (15 pmol x min-1 x g-1 liver), respectively. In parallel, lactate uptake rates (in micromol x min-1 x g-1 liver) were higher in the presence of both glucagon (0.90 +/- 0. 03) and leptin (0.84 +/- 0.02) compared with control (0.68 +/- 0.04). In conclusion, leptin modulates hepatic glucose fluxes and may contribute to direct humoral regulation of liver glycogen stores in the fasted as well as in the fed state.