Thermogenic effects of sibutramine and its metabolites

1 The thermogenic activity of the serotonin and noradrenaline reuptake inhi bitor sibutramine (BTS 54524; Reductil) was investigated by measuring oxyge n consumption (VO2) in rats treated with sibutramine or its two pharmacolog ically-active metabolites. 2 Sibutramine caused a dose-dependent rise in VO2, with a dose of 10 mg kg( -l) of sibutramine or its metabolites producing increases of up to 30% that were sustained for at least 6 h, and accompanied by significant increases (0.5-1.0 degrees C) in body temperature. 3 Based on the accumulation in vivo of radiolabelled 2-deoxy-[H-3]-glucose, sibutramine had little or no effect on glucose utilization in most tissues , but caused an 18 fold increase in brown adipose tissue (BAT). 4 Combined high, non-selective doses (20 mg kg(-1)) of the P-adrenoceptor a ntagonists, atenolol and ICI 118551, inhibited completely the VO2 response to sibutramine, but the response was unaffected by low, beta(1)-adrenocepto r-selective (atenolol) or beta(2)-adrenoceptor-selective (ICI 118551) doses (1 mg kg(-1)). 5 The ganglionic blocking agent, chlorisondamine (15 mg kg(-1)), inhibited completely the VO2 response to the metabolites of sibutramine, but had no e ffect on the thermogenic response to the beta(3)-adrenoceptor-selective ago nist BRL 35135. 6 Similar thermogenic responses were produced by simultaneous injection of nisoxetine and fluoxetine at doses (30 mg kg(-1)) that had no effect on VO2 when injected individually. 7 It is concluded that stimulation of thermogenesis by sibutramine requires central reuptake inhibition of both serotonin and noradrenaline, resulting in increased efferent sympathetic activation of BAT thermogenesis via beta (3)-adrenoceptor, and that this contributes to the compound's activity as a n anti-obesity agent.