Serotonergic neurons are included in the regulation of eating behavior and energy metabolism. Dexfenfluramine (DF), a serotonin releaser and reuptake inhibitor, is known to reduce food intake and body weight and to improve the metabolic profile of obese subjects with and without metabolic complications such as type 2 diabetes. Due to cases of valvular heart diseases, DF was withdrawn from the market in 1997. However, serotonergic drugs are still used in clinical practice. We studied the hemodynamic and metabolic changes induced by in situ perfusion of inguinal subcutaneous adipose tissue (SAT) of normal-weight rats with either 1 microM isoproterenol (IP) or 5 microM DF using the microdialysis technique. Perfusion of SAT with IP resulted in an increase in blood flow (+25%) and lipolysis (+35%) when compared to baseline. In contrast to that, perfusion of SAT with DF resulted in a decrease in blood flow (-25%) and lipolysis (-35%). Additionally, dialysate glucose was decreased and dialysate lactate was increased during perfusion with DF, indicating stimulation of glucose uptake and the glycolytic pathway. It is concluded that DF reduces blood flow and lipolysis whereas it stimulates the glycolytic pathway in SAT and that this could contribute to the positive metabolic outcome, i.e., lowered blood lipids and fat mass of DF-treated obese subjects.