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).
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References
Stock MJ . Sibutramine: a review of the pharmacology of a novel anti-obesity agent Int J Obes Relat Metab Disord 1997 21 (Suppl 1): S25–S29.
Heal DJ, Cheetham SC . The pharmacology of sibutramine, the first serotonin and noradrenaline reuptake inhibitor to be developed for the treatment of obesity Lettre Pharmac 1997 11 (Suppl 10): 3–8.
Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC . Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine Int J Obes Relat Metab Disord 1998 22 (Suppl 1): S18–S28.
Cheetham SC, Viggers JA, Slater NA, Heal DJ, Buckett WR . [3H]Paroxetine binding in rat frontal cortex strongly correlates with [3H]-5-HT uptake: effect of administration of various antidepressant treatments Neuropharmacology 1993 32: 737–743.
Cheetham SC, Viggers JA, Butler SA, Prow MR, Heal DJ . [3H]Nisoxetine—a radioligand for noradrenaline reuptake sites: correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments Neuropharmacology 1996 35: 63–70.
Luscombe GP, Hopcroft RH, Thomas PC, Buckett WR . The contribution of metabolites to the rapid and potent down-regulation of rat cortical β-adrenoceptors by the putative antidepressant sibutramine hydrochloride Neuropharmacology 1989 28: 129–134.
Jackson HC, Bearham MC, Hutchins LJ, Mazurkiewicz SE, Needham AM, Heal DJ . Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rats Br J Pharmac 1997 121: 1613–1618.
Jackson HC, Needham AM, Hutchins LJ, Mazurkiewicz SE, Heal DJ . Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat Br J Pharmac 1997 121: 1758–1762.
Grignaschi G, Fanelli E, Scagnol I, Samanin R . Studies on the role of serotonin receptor subtypes in the effect of sibutramine in various feeding paradigms in rats Br J Pharmac 1999 127: 1190–1194.
Halford JCG, Heal DJ, Blundell JE . Effects in the rats of sibutramine on food intake and the behavioural satiety sequence Br J Pharmac 1995 114: 387P.
Pleasance IM, Mitchell JC, Jackson HC, Heal DJ . Observational analysis of the effects of sibutramine and phentermine on food intake Int J Obes Relat Metab Disord 2000 24 (Suppl 1): P407.
Fantino M, Martel P, Souquet AM, Wieteska L, Brondel L, Courcier S . Decrease of food intake and weight loss induced by sibutramine in the rat Obes Res 1995 3 (Suppl 4): 628S.
Weintraub M, Rubio A, Golik A, Byrne L, Scheinbaum ML . Sibutramine in weight control; a dose-ranging efficacy study Clin Pharmac Ther 1991 50: 330–337.
Apfelbaum M, Vague P, Zeigler O, Hanotin C, Thomas F, Leutenegger E . Long-term maintenance of weight loss after a very low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine Am J Med 1999 106: 179–184.
James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WHM, Van Gaal LF . Effect of sibutramine on weight maintenance after weight loss: a randomised trial Lancet 2000 356: 2119–2125.
Connoley IP, Heal DJ, Stock MJ . A study in rats of the effects of sibutramine on food intake and thermogenesis Br J Pharmac 1995 114: 388P.
Connoley IP, Liu YL, Frost I, Reckless IP, Heal DJ, Stock MJ . Thermogenic effects of sibutramine and its metabolites Br J Pharmac 1999 126: 1487–1495.
Carlisle HJ, Stock MJ . Effect of conventional (mixed β1/β2) and novel (β3) adrenergic agonists on thermoregulatory behavior Pharmac Biochem Behav 1991 40: 249–254.
Hjorth S, Clark D, Carlsson A . Lack of functional evidence for the involvement of sigma opiate receptors in the actions of the 3-PPP enantiomers on central dopaminergic systems: discrepancies between in vitro and in vivo observations Life Sci 1985 37: 673–684.
Sakaguchi T, Bray GA . Effect of norepinephrine, serotonin and tryptophan on the firing of sympathetic nerves Brain Res 1989 492: 271–280.
Steiner G, Evans S . Effect of serotonin on BAT and on its sympathetic neurons Am J Physiol 1976 231: 34–39.
Plata-Salaman CR . Hypothalamus and the control of feeding: fifteen decades of direct association Nutrition 1998 14: 67–70.
Buckett WR, Luscombe GP, Thomas PC . BTS 54 524—an approach to a rapid acting antidepressant In: Briley M, Fillion G (eds.) New Concepts in Depression London: Macmillan 1987 pp 167–172.
Hoyer D . Functional correlates of serotonin 5-HT1 recognition sites J Receptor Res 1988 8: 59–81.
Hoyer D, Waeber C, Schoeffter P, Palacios JM, Dravid A . 5-HT1c receptor-mediated stimulation of inositol phosphate production in pig choroid plexus: a pharmacological characterization Naunyn-Schmiedeberg's Arch Pharmac 1989 339: 252–258.
Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphreys PPA . International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin) Pharmac Rev 1996 46: 157–203.
Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PAJ . Receptor binding profile of R 41468, a novel antagonist at 5-HT2 receptors Life Sci 1981 28: 1015–1022.
Carlisle HJ, Stock MJ . Potentiation of thermoregulatory responses to isoproterenol by β-adrenergic antagonists Am J Physiol 1992 263: R915–R923.
Liu Y-L, Stock MJ . Acute effects of the β3-adrenoceptor agonist BRL35135 on tissue glucose utilization Br J Pharmac 1995 114: 888–894.
Hume SP, Ashworth S, Lammertsma AA, Opacka-Juffry J, Law MP, McCarron JA, Clark RD, Nutt DJ, Pike VW . Evaluation in rat of RS-79948-197 as a potential PET ligand for central α2-adrenoceptors Eur J Pharmac 1996 317: 67–73.
Uhlen S, Dambrova M, Nasman J, Schioth HB, Gu Y, Wikberg-Matsson A, Wikberg JE . [3H]RS79948-197 binding to human, rat, guinea pig and pig alpha2A-, alpha2B- and alpha2C-adrenoceptors. Comparison with MK912, RX821002, rauwolscine and yohimbine Eur J Pharmac 1998 343: 93–101.
Galitzky J, Vermonel M, Lafontan M, Montastruc P, Berlan M . Thermogenic and lipolytic effect of yohimbine in the dog Br J Pharmac 1991 104: 514–518.
Laverty R, Taylor KM . Behavioural and biochemical effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155) on the central nervous system Br J Pharmac 1969 35: 253–264.
Drew GM, Gower AJ, Marriott AS . α2-Adrenoceptors mediate clonidine-induced sedation in the rat Br J Pharmac 1979 67: 133–141.
Zhao J, Cannon B, Nedergaard J . α1-Adrenergic stimulation potentiates the thermogenic action of β3-adrenoceptor-generated cAMP in brown fat cells J Biol Chem 1997 272: 32847–32856.
Skill MJ, Dickinson K, Jones RB, Heal DJ . Thermogenic effects of repeated sibutramine treatment in female rats Int J Obes Relat Metab Disord 2000 24 (Suppl 1): S135.
Burlet C, Stricker-Krongrad A, Souquet AM, Courcier S . Effects of chronic sibutramine treatment on feeding behaviour and body weight in adult rats Obes Res 1995 3: 627S.
Acknowledgements
The authors wish to thank Knoll Ltd Research & Development (Nottingham) for their financial support and for providing M2.
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Liu, YL., Heal, D. & Stock, M. Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine. Int J Obes 26, 1245–1253 (2002). https://doi.org/10.1038/sj.ijo.0802062
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DOI: https://doi.org/10.1038/sj.ijo.0802062