Energy Expenditure and Substrate Oxidation Rates of Obese Rats during a 12-Day Treatment with Dexfenfluramine

Abstract

Serotoninergic neuronal networks are included in regulation and modification of eating behavior and energy metabolism. Dexfenfluramine (dF), a serotonin releaser and reuptake inhibitor, was used to investigate changes in food intake, body weight development, energy expenditure, respiratory quotient, and substrate oxidation rates for 12 days. Rats which had been made obese by postnatal overfeeding received an energy-controlled mash diet and water ad libitum and were intraperitoneally injected with either saline or 5 or 10 mg dF/kg. As compared with controls, food intake and energy expenditure were significantly decreased in a dose-dependent manner, especially during the first 6 days. Lipid oxidation was increased, while the oxidation of carbohydrates was decreased. The body weight was only slightly reduced after 2 days of dF treatment. After 4 days, dF-treated rats resumed body weight, but as compared with controls both dF groups exhibited lower body weights at the end of the experiment. After 12 days the plasma glucose concentration was unchanged, whereas plasma free fatty acids were significantly decreased. Plasma insulin levels were unchanged after dF, but 10 mg dF/kg led to increased muscle and, especially, liver glycogen contents, indicating an improved nonoxidative glucose disposal. Muscle pyruvate kinase was slightly but not significantly increased after dF treatment but that of the liver was significantly decreased, indicating a reduced glycolytic activity of the liver. Whereas the renal N excretion was rather decreased, the plasma concentrations of urea, citrulline, arginine, and ornithine were increased, and the liver contents of glutamine and arginine were decreased. Possibly, there is a shift of ammonia removal from glutamine synthesis to production of urea. The sum of all large neutral amino acids in muscle was significantly decreased after dF treatment, indicating a diminished proteolysis. Pair-feeding experiments over 2 days revealed that this was not solely a result of diminished food intake, but also an additional metabolic effect of dF, different from its anorectic effect. It is concluded that both increased oxidation of endogenous fat and reduced food intake could mediate the body weight reducing effect of dF.

In situ Metabolic and Hemodynamic Response to Dexfenfluramine in White Adipose Tissue of Rats

“…We have reported an immediate decrease in energy expenditure and an increase in fat oxidation rate after administration of DF to normal and obese rats [22,23]. Additionally, we found a shift of glycolytic activity from liver to muscle and, overall, a carbohydrate-and protein-sparing effect of DF [24]. In isolated hepatocytes, insulin-like and glucagon-antagonizing effects of DF were found [25][26][27] while in isolated muscle cells, an insulin-permissive effect was described [28].…”