Tesofensine, a novel triple monoamine reuptake inhibitor, produces a significant weight loss in humans. The present study aimed at characterizing the weight-reducing effects of tesofensine in a rat model of diet-induced obesity. Sibutramine and rimonabant were used as reference comparators. Compared to baseline, long-term treatment with tesofensine (28 days, 1.0 or 2.5mg/kg, p.o.) resulted in a significant, dose-dependent and sustained weight loss of 5.7 and 9.9%, respectively. Sibutramine (7.5mg/kg, p.o.) treatment caused a sustained weight loss of 7.6%, whereas the employed dose of rimonabant (10mg/kg, p.o.) only produced a transient weight reduction. While all compounds exhibited a significant inhibitory effect on food intake which gradually wore off, the hypophagic effect of tesofensine was longer lasting than sibutramine and rimonabant. In contrast to tesofensine, the body weight of pair-fed rats returned to baseline at the end of the study, which may indicate that tesofensine stimulated energy expenditure. The differential efficacy on weight reduction was also reflected in lowered body fat depots, as tesofensine and sibutramine most efficiently reduced abdominal and subcutaneous fat mass which was paralleled by reduced plasma lipid levels. In an oral glucose tolerance test, only tesofensine significantly suppressed the plasma insulin response below the level that could be obtained by paired feeding, indicating that tesofensine further improved glycemic control. In conclusion, the robust weight loss with long-term tesofensine treatment is likely due to a combined synergistic effect of appetite suppression and increased energy expenditure.
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