The primary amine metabolite of sibutramine stimulates lipolysis in adipocytes isolated from lean and obese mice and in isolated human adipocytes.
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.
Richardson
D K
DK
Division of Diabetes, Department of Medicine, The University of Texas Health Science Center at San Antonio, Texas 78229-3900, USA. richardsond2@uthscsa.edu
Jones
R B
RB
Bailey
C J
CJ
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000588:Amines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001067:Appetite Depressants / Q000378:metabolism* / Q000494:pharmacology*; D002469:Cell Separation; D003503:Cyclobutanes / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D009852:Omentum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000588:Amines; D001067:Appetite Depressants; D003503:Cyclobutanes; D005990:Glycerol; C058254:sibutramine