Download PDF
Horm Metab Res 2006; 38(11): 727-731
DOI: 10.1055/s-2006-955083
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

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

D. K. Richardson 1 , R. B. Jones 2 , C. J. Bailey 3
  • 1Division of Diabetes, Department of Medicine, The University of Texas Health Science Center at San Antonio, Texas, USA
  • 2Knoll Ltd. Research and Development, Nottingham, UK
  • 3School of Life and Health Sciences, Aston University, Birmingham, UK
Further Information

Publication History

Received 27 March 2006

Accepted after revision 27 June 2006

Publication Date:
16 November 2006 (online)

Also available at
    Permissions and Reprints

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
    PubMedGoogle Scholar
  • 2 Day C, Bailey CJ. Sibutramine update.  Brit J Dia. Vasc Dis. 2002;  2 392-397
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 5 Ryan DH. Clinical use of sibutramine.  Drugs Today (Barc). 2004;  40 41-54
    CrossrefPubMedGoogle Scholar
  • 6 Finer N. Sibutramine: its mode of action and efficacy.  Int J Obes Relat Metab Disord. 2002;  26 29-33
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 8 McNeely W, Goa KL. Sibutramine. A review of its contribution to the management of obesity.  Drugs. 1998;  56 1093-1124
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 13 Flatt PR, Bailey CJ. Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice.  Diabetologia. 1981;  20 573-577
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 15 Rodbell M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis.  J Biol Chem. 1964;  239 375-380
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 17 Wieland O. Glycerol UV method. In: Bergmeyer HU (ed). Methods of Enzymatic Analysis. London: Academic Press 1974: 1404-1409
    Google Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 24 Guo A, Johnson M, Jensen MD. Regional lipolytic responses to isoproterenol in women.  Am Physiol Soc. 1997;  273 108-112
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar

Correspondence

Dawn K. RichardsonPh.D. 

Division of Diabetes MC 7886·Department of Medicine·The University of Texas Health Science Center at San Antonio

7703 Floyd Curl Drive

San Antonio

Texas 78229-3900

USA

Phone: +1/210/567 0336

Fax: +1/210/567 6554

Email: richardsond2@uthscsa.edu

      >