Fenfluramine Effects on Insulin Resistance and Lipogenesis in Genetically Obese (ob/ob) Mice

Abstract

Abstract

Treatment of 15-week-old obese and lean mice with the amphetamine derivative fenfluramine (15, 25, and 40 mg/kg body wt, ip) for 14 days did not reduce body weight, except in lean mice receiving 40 mg/kg. In vivo insulin sensitivity, measured as the ability of exogenous insulin (1 IU/kg body wt, ip) to lower blood glucose, was improved in obese mice receiving the two higher doses (25 and 40 mg/kg) of fenfluramine for 14 days, when compared to untreated obese mice. There was no change in insulin sensitivity between treated and untreated lean mice. This improvement, seen in obese mice which did not lose weight, demonstrates an effect of this drug distinct from its anorexigenic properties. On Day 21 of fenfluramine treatment, the in vivo rates of fatty acid synthesis were determined by injecting ³H₂O ip and measuring the amount of ³H incorporated into fatty acids over a 1-hr period. The rates of fatty acid synthesis per gram of liver and adipose tissue of obese and lean mice receiving 40 mg/kg fenfluramine were unchanged when compared to sham-injected controls. However, fat depletion was observed in epididymal fat pads of treated (40 mg/kg) lean mice, indicating either reduced lipid deposition or stimulated lipolysis in this group. In vitro, a therapeutic concentration (100 ng/ml) of fenfluramine increased insulin-stimulated conversion of [U-¹⁴C]glucose to fatty acids but not CO₂ and total lipids in isolated adipocytes from lean but not obese mice. These results indicate that the reduction of insulin resistance in obese mice treated with fenfluramine does not influence rates of lipogenesis in liver and adipose tissue but may be associated with increased insulin sensitivity of other tissues such as muscle.