Acute effects of leptin on glucose metabolism of in situ rat perfused livers and isolated hepatocytes

OBJECTIVE: To investigate whether leptin interferes directly with glycogenolysis and gluconeogenesis in isolated rat hepatocytes and also in in situ rat perfused livers. ANIMALS: Male albino rats (200-250 g) were used in all experiments. MEASUREMENTS: D-glucose, L-lactate and pyruvate production. RESULTS: In the present study, no differences were found for the rates of glycolysis, as expressed by the areas under the curves, among control (24.2 ± 5.0 mmol/g), leptin (32.0 ± 4.5 mmol/g), glucagon (24.7 ± 3.0 mmol/g), and the leptin + glucagon (23.8 ± 3.4 mmol/g) groups. No difference was found for the rates of glycogenolysis between the control and the leptin perfused livers (15.2 ± 3.9 and 15.0 ± 3.2 mmol/g, respectively). In the presence of glucagon, the areas under the curves for the rate of glycogenolysis rose to 108.6 ± 3.8 mmol/g. When leptin was combined with glucagon, the area under the curve for glycogenolysis was 43.7 ± 4.3 mmol/g. In fact, leptin caused a reduction of almost 60% (P < 0.001) in the rate of glucagon-stimulated glycogenolysis. Under basal conditions, the addition of leptin (100 ng/ml) to the incubation medium did not elicit any alteration in glucose production by isolated hepatocytes. However, in the presence of leptin, the production of glucose from glycerol (2 mM), L-lactate (2 mM). L-alanine (5 mM) and L-glutamine (5 mM) by the isolated hepatocytes was significantly reduced (30%, 30%, 23% and 25%, respectively). The rate of glucose production (glycogenolysis) by isolated hepatocytes was not different between the control and the leptin incubated groups (445.0 ± 91.0 and 428.0 ± 72.0 nmol/10⁶ cells/h, respectively). CONCLUSION: We conclude that leptin per se does not directly affect either liver glycolysis or its glucose production, but a physiological leptin concentration is capable of acutely inducing a direct marked reduction on the rate of glucagon-stimulated glucose production in in situ rat perfused liver. Leptin is also capable of reducing glucose production from different gluconeogenic precursors in isolated hepatocytes.