Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Abstract

OBJECTIVE: To investigate the pharmacological mechanisms underlying the induction of thermogenesis by Metabolite 2 (M2; BTS 54 505), a major pharmacologically active metabolite of the anti-obesity drug, sibutramine.

DESIGN: Adult female Wistar rats were treated with M2 or vehicle, with or without various monoamine receptor antagonists, prazosin, RS79948, metergoline, propranolol and (+)butaclamol.

MEASUREMENTS: Colonic temperature and food intake at room temperature (21±1°C), thermoregulatory behavioural response, operant responding for exogenous heat at −8°C and oxygen consumption at thermoneutrality (29°C).

RESULTS: M2 (10 mg/kg, p.o.) significantly increased colonic temperature during the 4.5 h period following drug administration. This effect was abolished by the non-selective 5-HT receptor antagonist, metergoline (1 mg/kg, p.o.), and α₁-adrenoceptor antagonist, prazosin (1 mg/kg, p.o.), measured at 1.5–2.5 h post-M2 administration, and was partially antagonized by each antagonist at 3.5–4.5 h. The non-selective β-adrenoceptor antagonist, propranolol (1 mg/kg, p.o.), had no effect on the M2-induced increase in colonic temperature, whereas at 20 mg/kg (p.o.), propranolol partially inhibited the effect of M2 on colonic temperature. By contrast, the selective α₂-adrenoceptor antagonist, RS79948 (1 mg/kg, p.o.), and the D2/D1 receptor antagonist, (+)butaclamol (200 µg/kg, p.o.), did not alter the effect of M2 on colonic temperature. In the thermoregulatory study, M2 (10 mg/kg, i.p.)-treated rats required significantly less radiant heat at −8°C to maintain body temperature, and this effect was not affected by the D2/D1 receptor antagonist (+)butaclamol (100 µg/kg⁻¹, i.p.). The hypophagia induced by M2 (10 mg/kg) measured up to 24 h was partially antagonized by the α₁-adrenoceptor antagonist, prazosin, whereas metergoline, RS79948, propranolol and (+)butaclamol had no effect on M2-induced hypophagia.

CONCLUSION: It is concluded that 5-HT, α₁- and β₃-adrenoceptors are involved in the induction of thermogenesis by M2, whereas the hypophagic effect is mainly mediated via α₁-adrenoceptors. These findings are consistent with M2 increasing 5-HT and noradrenaline tone via potent reuptake inhibition which subsequently results in increased efferent sympathetic activity to brown adipose tissue (BAT).