Effect of diet and fenfluramine on thermogenesis in the rat: Possible involvement of serotonergic mechanisms

A single injection of 5-hydroxytryptamine (5HT, 1 mg/kg, s.c.) in rats stimulated resting oxygen consumption (V̇o2) by 21 percent; this was reduced (to 8 percent) by pretreatment with hexamethonium (5 mg/kg, s.c.). DL-fenfluramine injection (20 mg/kg, s.c.) stimulated metabolic rate (V̇o2) by about 40 percent, but caused only 11 and 15 per cent increases in animals pretreated with hexamethonium or metergoline (5 mg/kg, s.c.), respectively. Interscapular brown adipose tissue (BAT) activity, assessed from mitochondrial GDP-binding, was increased by 96 per cent in intact tissue 1 h after fenfluramine injection; this response was completely prevented by surgical sympathectomy of interscapular BAT. Metergoline significantly inhibited (by 46 percent) the acute thermic response (postprandial rise in V̇o2) to a 40-kJ meal in normal rats, and depressed resting V̇o2 in protein-deficient rats by 18 percent, but did not affect resting V̇o2 in control animals. BAT activity (mitochondrial GDP-binding) was elevated by 56 per cent in rats fed the low-protein diet, but this difference was almost completely abolished by prior treatment with metergoline. These data demonstrate a potent thermogenic effect of fenfluramine which apparently involves serotonergic pathways and activation of sympathetic outflow to BAT, and indicate that acute thermic responses to food and chronic thermogenic responses to low-protein diets may also involve serotonergic mechanisms.