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


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


METHODS
Colonic temperature and food intake at room temperature (21+/-1 degrees C), thermoregulatory behavioural response, operant responding for exogenous heat at -8 degrees C and oxygen consumption at thermoneutrality (29 degrees 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 alpha(1)-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 beta-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 alpha(2)-adrenoceptor antagonist, RS79948 (1 mg/kg, p.o.), and the D2/D1 receptor antagonist, (+)butaclamol (200 micro g/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 degrees C to maintain body temperature, and this effect was not affected by the D2/D1 receptor antagonist (+)butaclamol (100 micro g/kg(-1), i.p.). The hypophagia induced by M2 (10 mg/kg) measured up to 24 h was partially antagonized by the alpha(1)-adrenoceptor antagonist, prazosin, whereas metergoline, RS79948, propranolol and (+)butaclamol had no effect on M2-induced hypophagia.


CONCLUSIONS
It is concluded that 5-HT, alpha(1)- and beta(3)-adrenoceptors are involved in the induction of thermogenesis by M2, whereas the hypophagic effect is mainly mediated via alpha(1)-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).
Department of Physiology, St George's Hospital Medical School, University of London, UK. yliu@sghms.ac.uk
Y-L
YL
Liu
D J
DJ
Heal
M J
MJ
Stock
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001067:Appetite Depressants / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D003503:Cyclobutanes / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005260:Female; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology; D022722:Thermogenesis / Q000187:drug effects*; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D003503:Cyclobutanes; D018492:Dopamine Antagonists; D012702:Serotonin Antagonists; C087851:BTS 54 505; C058254:sibutramine