Horm Metab Res 2002; 34(9): 475-480
DOI: 10.1055/s-2002-34786
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Effects of the G-Protein β3 Subunit 825T Allele on Adipogenesis and Lipolysis in Cultured Human Preadipocytes and Adipocytes

H.  Hauner 1 , K.  Röhrig 1 , W.  Siffert 2
  • 1Deutsches Diabetes-Forschungsinstitut an der Heinrich-Heine-Universität Düsseldorf, Germany
  • 2Institut für Pharmakologie, Universitätsklinikum Essen, Germany
Further Information

Publication History

Received: 31 January 2002

Accepted after revision: 22 April 2002

Publication Date:
17 October 2002 (online)

Abstract

The recently discovered C825T polymorphism of the G-protein β3 subunit has been reported to be associated with the development of hypertension and obesity. The aim of our study was to investigate the relationship between the C825T polymorphism and functional aspects of human adipose cells, particularly with regard to adipose differentiation and lipolysis. Adipose tissue samples were collected from 65 women with a BMI ranging from 19.7 to 39.7 kg/m2 undergoing surgical mammary reduction. The stromal cells were allowed to undergo differentiation in primary culture using adipogenic media of defined composition. No significant difference was observed between the CC carriers and the carriers of the T allele under all adipogenic conditions with differentiation capacity related to the genotype. In a subgroup of patients (n = 20), lipolysis in isolated fat cells was determined by measurement of glycerol in the culture medium upon catecholamine exposure. Glycerol release after 10-7 mmol/l isoproterenol was significantly higher in fat cells from the 10 CC carriers than in adipocytes from the T allele carriers when expressed as percentage of basal glycerol release (increase above baseline: CC: 809 ± 174 %, T allele carriers: 247 ± 88 %, p = 0.01), while basal glycerol concentrations were no different according to genotype after controlling for either age or BMI. In conclusion, this study provides the first evidence that the GNB3 825T allele is associated with an impairment of the β-adrenergic control of lipolysis.

References

  • 1 Farfel Z, Bourne H R, Iiri T. The expanding spectrum of G protein diseases.  N Engl J Med. 1999;  340 1012-1020
  • 2 Siffert W, Rosskopf D, Siffert G. et al . Association of a human G-protein beta3 subunit variant with hypertension.  Nature Genet. 1998;  18 45-48
  • 3 Dong Y, Zhu H, Sagnella G A, Carter N D, Cook D G, Cappuccio F P. Association between the C825T polymorphism of the G Protein beta3-subunit gene and hypertension in blacks.  Hypertension. 1999;  34 1193-1196
  • 4 Hengstenberg C, Schunkert H, Mayer B, Döring A, Löwel H, Hense H, Fischer M, Riegger G A, Holmer S R. Association between a polymorphism in the G protein beta3 subunit gene (GNB3) with arterial hypertension but not with myocardial infarction.  Cardiovasc Res. 2001;  49 820-827
  • 5 Schunkert H, Hense H W, Döring A, Riegger G AJ, Siffert W. Association between a polymorphism in the G protein β3 subunit gene and lower renin and elevated diastolic blood pressure.  Hypertension. 1998;  32 510-513
  • 6 Siffert W, Forster P, Jöckel K-H. et al . Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals.  J Am Soc Nephrol. 1999;  10 1921-1930
  • 7 Siffert W, Naber C, Walla M, Ritz E. G protein β3 subunit 825 T allele and its potential association with obesity in hypertensive patients.  J Hypertens. 1999;  17 1095-1098
  • 8 Hegele R A, Anderson C, Young T K, Connelly P W. G-protein beta3 subunit gene splice variant and body fat distribution in Nunavut Inuit.  Genome Res. 1999;  9 972-977
  • 9 Benjafield A V, Lin R C, Dalziel B, Gosby A K, Caterson I D, Morris B J. G-protein beta3 subunit gene splice variant in obesity and overweight.  Int J Obes Relat Metab Disord. 2001;  25 777-780
  • 10 Gutersohn A, Naber C, Müller N, Erbel R, Siffert W. G protein beta3 subunit 825 TT genotype and post-pregnancy weight retention.  Lancet. 2000;  355 1240-1241
  • 11 Ailhaud G, Hauner H. Development of white adipose tissue. In: Bray GA, Bouchard C, James WPT (eds) “Handbook of Obesity”. New York; Marcel Dekker 1998: 359-378
  • 12 Wang H-Y, Malbon C C. The Gsa/Gia2 axis controls adipogenesis independently of adenylylcyclase.  Int J Obes Relat Metab Disord. 1996;  20, Suppl. 3 S26-S31
  • 13 Bouloumie A, Planat V, Devedjian J-C h, Valet P, Saulnier-Blache J-S, Record M, Lafontan M. α2-adrenergic stimulation promotes preadipocyte proliferation. Involvement of mitogen-activated protein kinases.  J Biol Chem. 1994;  269 30 254-30 259
  • 14 Arner P, Eckel R H. Adipose tissue as a storage organ. In: Bray GA, Bouchard C, James WPT (eds) “Handbook of Obesity”. New York; Marcel Dekker 1998: 379-396
  • 15 Moxham C M, Malbon C C. Insulin action impaired by deficiency of the G-protein subunit Giα2.  Nature. 1996;  379 840-844
  • 16 Chen J F, Guo J H, Moxham C M, Wang H Y, Malbon C C. Conditional, tissue-specific expression of Q205L G alpha i2 in vivo mimics insulin action.  J Mol Med. 1997;  75 283-289
  • 17 Virchow S, Ansorge N, Rosskopf D, Rübben H, Siffert W. The G protein beta3 subunit splice variant Gbeta3-s causes enhanced chemotaxis of human neutrophils in response to interleukin-8.  Naunyn Schmiedebergs Arch Pharmacol. 1999;  360 27-32
  • 18 Hauner H, Entenmann G, Wabitsch M, Gaillard D, Ailhaud G, Negrel R, Pfeiffer E F. Promoting effects of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium.  J Clin Invest. 1989;  84 1663-1670
  • 19 Pairault J, Green H. A study of the adipose conversion of suspended 3T3 cells by using glycerophosphate dehydrogenase as differentiation marker.  Proc Natl Acad Sci USA. 1979;  76 5138-5142
  • 20 Gottschling-Zeller H, Birgel M, Scriba D, Blum W F, Hauner H. Depot-specific release of leptin from subcutaneous and omental adipocytes in suspension culture: effect of tumor necrosis factor-α and transforming growth factor-β.  Eur J Endocrinol. 1999;  141 436-442
  • 21 Hellmer J, Arner P, Lundin A. Automatic luminometric kinetic assay of glycerol for lipolysis studies.  Anal Biochem. 1989;  177 132-137
  • 22 Siffert W. G protein β3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy.  Nephrol Dial Transplant. 2000;  15 1298-1306
  • 23 Baumgart D, Naber C, Haude M, Oldenburg O, Erbel R, Heusch G, Siffert W. G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on alpha(2)-adrenoceptor activation.  Circ Res. 1999;  85 965-969
  • 24 Naber C, Hermann B L, Vietzke D, Altmann C, Haude M, Mann K, Rosskopf D, Siffert W. Enhanced epinephrine-induced platelet aggregation in individuals carrying the G protein beta3 subunit 825T allele.  FEBS Lett. 2000;  484 199-201
  • 25 Fain J N, Garcia-Sainz J A, Mills I, O’Donnell C J. Activation of lipolysis and cyclic AMP accumulation in rabbit adipocytes by isoproterenol in the presence of forskolin or pertussis toxin.  Biochim Biophys Acta. 1984;  798 382-389
  • 26 Schimmel R J, McCarthy L, Dzierzanowski D. Effects of pertussis toxin treatment on metabolism in hamster brown adipocytes.  Am J Physiol. 1985;  249 C456-C463
  • 27 Wesslau C, Smith U. The inhibitory GTP-binding protein (Gi) regulates the agonistic property of beta-adrenergic ligands in isolated rat adipocytes. Evidence for a priming effect of cyclic AMP.  Biochem J. 1992;  288 41-46
  • 28 Goren H J, Northup J K, Hollenberg M D. Action of insulin modulated by pertussis toxin in rat adipocytes.  Can J Physiol Pharmacol. 1985;  63 1017-1022
  • 29 Wenzel-Seifert K, Seifert R. Molecular analysis of beta(2)-adrenoceptor coupling to G(s)-, G(i)-, and G(q)-proteins.  Mol Pharmacol. 2000;  58 954-966
  • 30 Xiao R P, Avdonin P, Zhou Y Y, Cheng H, Akhter S A, Eschenhagen T, Lefkowitz R J, Koch W J, Lakatta E G. Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes.  Circ Res. 1999;  84 43-52
  • 31 Soeder K J, Snedden S K, Cao W, Della Rocca G J, Daniel K W, Luttrell L M, Collins S. The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism.  J Biol Chem. 1999;  274 12 017-12 022

H. Hauner, M.D.

German Diabetes Research Institute

Heinrich-Heine-University Düsseldorf · Auf’m Hennekamp 65 · 40225 Düsseldorf · Germany

Email: hauner@ddfi.uni-duesseldorf.de

    >