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).
Liu
Y-L
YL
Department of Physiology, St George's Hospital Medical School, University of London, UK. yliu@sghms.ac.uk
Heal
D J
DJ
Stock
M J
MJ
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