The Primary Amine Metabolite of Sibutramine Stimulates Lipolysis in Adipocytes Isolated from Lean and Obese Mice and in Isolated Human Adipocytes

Abstract

Sibutramine is a satiety-inducing serotonin-noradrenaline reuptake inhibitor that acts predominantly via its primary and secondary metabolites. This study investigates the possibility that sibutramine and/or its metabolites could act directly on white adipose tissue to increase lipolysis. Adipocytes were isolated by a collagenase digestion procedure from homozygous lean (+/+) and obese-diabetic ob/ob mice, and from lean nondiabetic human subjects. The lipolytic activity of adipocyte preparations was measured by the determination of glycerol release over a 2-hour incubation period. The primary amine metabolite of sibutramine M2, caused a concentration-dependent stimulation of glycerol release by murine lean and obese adipocytes (maximum increase by 157±22 and 245±16%, respectively, p<0.05). Neither sibutramine nor its secondary amine metabolite M1 had any effect on lipolytic activity. Preliminary studies indicated that M2-induced lipolysis was mediated via a beta-adrenergic action. The non-selective beta-adrenoceptor antagonist propranolol (10^-6 M) strongly inhibited M2-stimulated lipolysis in lean and obese murine adipocytes. M2 similarly increased lipolysis by isolated human omental and subcutaneous adipocytes (maximum increase by 194±33 and 136±4%, respectively, p<0.05) with EC50 values of 12 nM and 3 nM, respectively. These results indicate that the sibutramine metabolite M2 can act directly on murine and human adipose tissue to increase lipolysis via a pathway involving beta-adrenoceptors.

Key words

Sibutramine - M2 - lipolysis - white adipose tissue - β-adrenoceptors

References

• 1 Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC. Meta-analysis: pharmacologic treatment of obesity.  Ann Intern Med. 2005;  142 532-546
• 2 Day C, Bailey CJ. Sibutramine update.  Brit J Dia. Vasc Dis. 2002;  2 392-397
• 3 Filippatos TD, Kiortsis DN, Liberopoulos EN, Mikhailidis DP, Elisaf MS. A review of the metabolic effects of sibutramine.  Curr Med Res Opin. 2005;  21 457-468
• 4 Tankova T, Dakovska G, Lazarova M, Dakovska L, Kirilov G, Koev D. Sibutramine in the treatment of obesity in type 2 diabetic patients and in nondiabetic subjects.  Acta Diabetol. 2004;  41 146-153
• 5 Ryan DH. Clinical use of sibutramine.  Drugs Today (Barc). 2004;  40 41-54
• 6 Finer N. Sibutramine: its mode of action and efficacy.  Int J Obes Relat Metab Disord. 2002;  26 29-33
• 7 Vettor R, Serra R, Fabris R, Pagano C, Federspil G. Effect of sibutramine on weight management and metabolic control in type 2 diabetes: a meta-analysis of clinical studies.  Diabetes Care. 2005;  28 942-949
• 8 McNeely W, Goa KL. Sibutramine. A review of its contribution to the management of obesity.  Drugs. 1998;  56 1093-1124
• 9 Bailey CJ, Turner SL, Bates SH, Jones RB. Sibutramine metabolites increase glucose transport by cultured rat muscle cells.  Int J Obes Relat Metab Disord. 2001;  25 478-485
• 10 Liu YL, Heal DJ, Stock MJ. 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 Relat Metab Disord. 2002;  26 1245-1253
• 11 Liu YL, Connoley IP, Harrison J, Heal DJ, Stock MJ. Comparison of the thermogenic and hypophagic effects of sibutramine's metabolite 2 and other monoamine reuptake inhibitors.  Eur J Pharmacol. 2002;  452 49-56
• 12 Day C, Bailey CJ. Effect of the antiobesity agent sibutramine in obese-diabetic ob/ob mice.  Int J Obes Relat Metab Disord. 1998;  22 619-623
• 13 Flatt PR, Bailey CJ. Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice.  Diabetologia. 1981;  20 573-577
• 14 Bailey CJ, Flatt PR, Atkins TW. Influence of genetic background and age on the expression of the obese hyperglycaemic syndrome in Aston ob/ob mice.  Int J Obes. 1982;  6 11-21
• 15 Rodbell M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis.  J Biol Chem. 1964;  239 375-380
• 16 Pederson O, Hjollund E, Beck-Nielson H, Linskov H, Sonne H, Gliemann J. Insulin receptor binding and receptor mediated insulin degradation in human adipocytes.  Diabetologia. 1981;  20 636-641
• 17 Wieland O. Glycerol UV method. In: Bergmeyer HU (ed). Methods of Enzymatic Analysis. London: Academic Press 1974: 1404-1409
• 18 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 Pharmacol. 1997;  121 1758-1762
• 19 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 18-28
• 20 Bray GA, Blackburn GL, Ferguson JM, Greenway FL, Jain AK, Mendel CM, Mendels J, Ryan DH, Schwartz SL, Scheinbaum ML, Seaton TB. Sibutramine produces dose-related weight loss.  Obes Res. 1999;  7 189-198
• 21 Chapelot D, Marmonier C, Thomas F, Hanotin C. Modalities of the food intake-reducing effect of sibutramine in humans.  Physiol Behav. 2000;  68 299-308
• 22 Barkeling B, Elfhag K, Rooth P, Rossner S. Short-term effects of sibutramine (Reductil) on appetite and eating behaviour and the long-term therapeutic outcome.  Int J Obes Relat Metab Disord. 2003;  27 693-700
• 23 Hansen DL, Toubro S, Stock MJ, Macdonald IA, Astrup A. Thermogenic effects of sibutramine in humans.  Am J Clin Nutr. 1998;  68 1180-1186
• 24 Guo A, Johnson M, Jensen MD. Regional lipolytic responses to isoproterenol in women.  Am Physiol Soc. 1997;  273 108-112
• 25 Galitzky J, Reverte M, Portillo M, Carpene C, Lafontan M, Berlan M. Coexistence of beta 1-, beta 2-, and beta 3-adrenoceptors in dog fat cells and their differential activation by catecholamines.  Am J Physiol. 1993;  264 403-412
• 26 Dujovne CA, Zavoral JH, Rowe E, Mendel CM. Sibutramine Study Group. Effects of sibutramine on body weight and serum lipids: a double-blind, randomized, placebo-controlled study in 322 overweight and obese patients with dyslipidemia.  Am Heart J. 2001;  142 489-497

Correspondence