Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Association of adipose tissue deposition and beta-2 adrenergic receptor variants: the IRAS family study

International Journal of Obesity volume 29, pages 449–457 (2005)Cite this article

Abstract

OBJECTIVE:

Adipose tissue distribution (visceral vs subcutaneous) has been shown to be an important predictor of insulin resistance, diabetes and cardiovascular disease, independent of body mass index. The beta-2 adrenergic receptor is a major lipolytic receptor in human fat cells and the gene that codes for this protein is an important candidate gene for measures of adiposity and fat deposition. We examined whether two common polymorphisms in codons 16 (Arg16Gly) and 27 (Gln27Glu) are associated with measures of fat distribution in participants of the IRAS Family Study.

METHODS:

We recruited African-American (AA) and Hispanic-American (HA) families from Los Angeles, CA, USA (18 pedigrees, 272 AA individuals), San Antonio, TX, USA (33 pedigrees, 448 HA individuals) and San Luis Valley, CO, USA (12 pedigrees, 272 HA individuals). We estimated adipose tissue distribution via computed tomography. To test for an association between adiposity measures and these polymorphisms, we used generalized estimating equations, adjusting for age, gender, clinical site (ethnicity), body mass index, and familial correlation.

RESULTS:

Of the 992 individuals genotyped for these polymorphisms, 57% were female and 15% had been diagnosed with type 2 diabetes mellitus. The mean age was 42.7±14.6 y. The Glu27 allele of the Gln27Glu polymorphism was positively associated with (P-value for recessive model): body mass index (0.025), visceral adipose tissue (<0.0001) and visceral-to-subcutaneous adipose ratio (0.009), but not with subcutaneous adipose tissue (0.952). The Arg16Gly polymorphism was not associated with any of the adiposity measures.

CONCLUSIONS:

These findings suggest that genetic variation in the beta-2 adrenergic receptor gene influences fat deposition and body size in AAs and HAs. In particular, these results support a role for the gene in the distribution of visceral adipose tissue but not subcutaneous adipose tissue.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G . Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. BMJ 1984; 288: 1401–1404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Prineas RJ, Folsom AR, Kaye SA . Central adiposity and increased risk of coronary artery disease mortality in older women. Ann Epidemiol 1993; 3: 35–41.

    Article  CAS  PubMed  Google Scholar 

  3. Visscher TL, Seidell JC, Molarius A, van der Kuip D, Hofman A, Witteman JC . A comparison of body mass index, waist-hip ratio and waist circumference as predictors of all-cause mortality among the elderly: the Rotterdam study. Int J Obes Relat Metab Disord 2001; 25: 1730–1735.

    Article  CAS  PubMed  Google Scholar 

  4. Oppert JM, Charles MA, Thibult N, Guy-Grand B, Eschwege E, Ducimetiere P . Anthropometric estimates of muscle and fat mass in relation to cardiac and cancer mortality in men: the Paris Prospective Study. Am J Clin Nutr 2002; 75: 1107–1113.

    Article  CAS  PubMed  Google Scholar 

  5. Bjorntorp P . Abdominal fat distribution and the metabolic syndrome. J Cardiovasc Pharmacol 1992; 20 (Suppl 8): S26–S28.

    Article  PubMed  Google Scholar 

  6. Kaplan NM . The deadly quartet: upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med 1989; 149: 1514–1520.

    Article  CAS  PubMed  Google Scholar 

  7. Rice T, Despres JP, Daw EW, Gagnon J, Borecki IB, Perusse L, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C . Familial resemblance for abdominal visceral fat: the HERITAGE family study, 1997; 21: 1024–1031.

    Article  CAS  PubMed  Google Scholar 

  8. Langefeld CD, Zaccaro DJ, Scherzinger AL, Norris MJ, Saad MF, Haffner SM, Wagenknecht LE, Rich SS . Familiality of visceral and subcutaneous fat. Diabetes 2001; 50 (Suppl 2): A241.

    Google Scholar 

  9. Kissebah AH, Krakower GR . Regional adiposity and morbidity. Physiol Rev 1994; 74: 761–811.

    Article  CAS  PubMed  Google Scholar 

  10. Liggett SB . Molecular and genetic basis of β2-adrenergic receptor function. J Allergy Clin Immunol 1999; 104: S42–S46.

    Article  CAS  PubMed  Google Scholar 

  11. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L, Arner P . Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 1997; 100: 3005–3013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Garenc C, Perusse L, Chagnon YC, Rankinen T, Gagnon J, Borecki IB, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C . Effects of β2-adrenergic receptor gene variants on adiposity: the HERITAGE Family Study. Obes Res 2003; 11: 612–618.

    Article  CAS  PubMed  Google Scholar 

  13. Corbalán MS, Marti A, Forga L, Martínez-González MA, Martínez JA . β2-adrenergic receptor mutation and abdominal obesity risk: effect modification by gender and HDL-cholesterol. Eur J Nutr 2002; 41: 114–118.

    Article  PubMed  Google Scholar 

  14. Hellstrom L, Large V, Reynisdottir S, Wahrenberg H, Arner P . The different effects of a Gln27Glu β2-adrenoceptor gene polymorphism on obesity in males and in females. J Int Med 1999; 245: 253–259.

    Article  CAS  Google Scholar 

  15. Mori Y, Kim-Motoyama H, Ito Y, Katakura T, Yasuda K, Ishiyama-Shigemoto S, Yamada K, Yasuo A, Ohashi Y, Kimura S, Yazaki Y, Kadowaki T . The Gln27Glu β2-adrenergic receptor variant is associated with obesity due to subcutaneous fat accumulation in Japanese men. Biochem Biophys Res Commun 1999; 258: 138–140.

    Article  CAS  PubMed  Google Scholar 

  16. Yamada K, Ishiyama-Shigemoto S, Ichikawa F, Yuan X, Koyanagi A, Koyama W, Nonaka K . Polymorphism in the 5′-leader cistron of the β2-adrenergic receptor gene associated with obesity and type 2 diabetes. J Clin Endocrinol Metab 1999; 84: 1754–1757.

    CAS  PubMed  Google Scholar 

  17. Bengtsson K, Orho-Melander M, Melander O, Lindblad U, Ranstam J, Råstam L, Groop L . 2 adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes. Hypertension 2001; 37: 1303–1308.

    Article  CAS  PubMed  Google Scholar 

  18. Green SA, Turki J, Innis M, Liggett SB . Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9419.

    Article  CAS  PubMed  Google Scholar 

  19. Bruck H, Leineweber K, Buscher R, Ulrich A, Radke J, Insel PA, Brodde O-E . The Gln27Glu β2-adrenergic receptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo. Pharmacogenetics 2003; 13: 59–66.

    Article  CAS  PubMed  Google Scholar 

  20. Gonzalez Sanchez JL, Proenza AM, Martinez Larrad MT, Ramis JM, Fernandez Perez C, Palou A, Serrano Rios M . The glutamine 27 glutamic acid polymorphism of the β2-adrenoceptor gene is associated with abdominal obesity and greater risk of impaired glucose tolerance in men but not in women: a population-based study in Spain. Clin Endocrinol 2003; 59: 476–481.

    Article  CAS  Google Scholar 

  21. Kawamura T, Egusa G, Fumikawa R, Okubo M . Gln27Glu variant of the beta-2 adrenergic receptor gene is not associated with obesity and diabetes in Japanese-Americans. Metabolism 2001; 50: 443–446.

    Article  CAS  PubMed  Google Scholar 

  22. Oberkofler H, Esterbauer H, Hell E, Krempler F, Patsch W . The GLn27Glu polymorphism in the beta2-adrenergic receptor gene is not associated with morbid obesity in Austrian women. Int J Obes Relat Metab Disord 2000; 24: 388–390.

    Article  CAS  PubMed  Google Scholar 

  23. Kortner B, Wolf A, Wendt D, Beiseigel U, Evans D . Lack of association between a human beta-2 adrenoceptor gene polymorphism (gln27glu) and morbid obesity. Int J Obes Relat Metab Disord 1999; 23: 1099–1100.

    Article  CAS  PubMed  Google Scholar 

  24. Echwald SM, Sorensen TI, Tybjaerg-Hansen A, Andersen T, Pedersen O . Gln27Glu variant of the human beta2-adrenoceptor gene is not associated with early-onset obesity in Danish men. Diabetes 1998; 47: 1657–1658.

    Article  CAS  PubMed  Google Scholar 

  25. Castellano M, Rossi F, Giacche M, Perani C, Rivadossi F, Muiesan ML, Salvetti M, Beschi M, Rizzoni D, Agabiti-Rosei E . Beta(2)-adrenergic receptor gene polymorphism, age, and cardiovascular phenotypes. Hypertension 2003; 41: 361–367.

    Article  CAS  PubMed  Google Scholar 

  26. Ukkola O, Tremblay A, Bouchard C . Beta-2 adrenergic receptor variants are associated with subcutaneous fat accumulation in response to long-term overfeeding. Int J Obes Relat Metab Disord 2001; 25: 1604–1608.

    Article  CAS  PubMed  Google Scholar 

  27. Ukkola O, Rankinen T, Rice T, Gagnon J, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C . Interactions among the β2- and β3-adrenergic receptor genes and total body fat and abdominal fat level in HERITAGE Family Study. Int J Obes Relat Metab Disord 2003; 27: 389–393.

    Article  CAS  PubMed  Google Scholar 

  28. Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD, Mitchell BD, Norris JM, Rewers M, Saad MF, Stamm E, Wagenknecht LE, Rich SS . Genetic epidemiology of insulin resistance and visceral adiposity: the IRAS Family Study Design and Methods. Ann Epidemiol 2003; 13: 211–217.

    Article  PubMed  Google Scholar 

  29. Bergman RN, Ider YZ, Bowden CR, Corbelli C . Quantitative estimation of insulin sensitivity. Am J Physiol 1979; 236: E667–77.

    CAS  PubMed  Google Scholar 

  30. Bergman RN, Finegood DT, Ader M . Assessment of insulin sensitivity in vivo. Endocr Rev 1985; 6: 45–86.

    Article  CAS  PubMed  Google Scholar 

  31. Steil GM, Volund A, Kahn SE, Bergman RN . Reduced sample number of calculation of insulin sensitivity and glucose effectiveness from the minimal model. Suitability for use in population studies. Diabetes 1993; 42: 250–256.

    Article  CAS  PubMed  Google Scholar 

  32. Buetow KH, Edmonson M, MacDonald R, Clifford R, Yip P, Kelley J, Little DP, Strausberg R, Koester H, Cantor CR, Braun A . High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Natl Acad Sci 2001; 16: 581–584.

    Article  Google Scholar 

  33. O’Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lewontin RC . An estimate of average heterozygosity in man. Am J Hum Genet 1967; 19: 681–685.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Zeger SL, Liang KY . Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: 121–130.

    Article  CAS  PubMed  Google Scholar 

  36. O’Connell JR . Zero-recombinant haplotyping: applications to fine mapping using SNPs. Genet Epidemiol 2000; 19 (Suppl 1): S64–S70.

    Article  PubMed  Google Scholar 

  37. O’Connell J . PROFILER: A program to compute cumulative probability profiles with applications to pedigree analysis. Am J Hum Genet 2000; 67: A1820.

    Google Scholar 

  38. Wajchenberg BL . Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21: 697–738.

    Article  CAS  PubMed  Google Scholar 

  39. Carey DG . Abdominal obesity. Curr Opin Lipidol 1998; 9: 35–40.

    Article  CAS  PubMed  Google Scholar 

  40. Arner P . Regional differences in protein production by human adipose tissue. Biochem Soc Trans 2001; 29 (Part 2): 72–75.

    Article  CAS  PubMed  Google Scholar 

  41. Arner P . Differences in lipolysis between human subcutaneous and omental adipose tissues. Ann Med 1995; 27: 860–867.

    Article  Google Scholar 

  42. Alessi M, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I . Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997; 46: 860–867.

    Article  CAS  PubMed  Google Scholar 

  43. Dusserre E, Moulin P, Vidal H . Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissue. Biochim Biophys Acta 2000; 1500: 88–96.

    Article  CAS  PubMed  Google Scholar 

  44. Montague C, Prins J, Sanders L, Zhang J, Sewter C, Digby J, Byrne J, O’Rahilly S . Depot-related gene expression in human subcutaneous and omental adipocytes. Diabetes 1998; 47: 1384–1390.

    Article  CAS  PubMed  Google Scholar 

  45. Lihn AS, Bruun JM, He G, Pedersen SB, Jensen PF, Richelsen B . Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Mol Cell Endocrinol 2004; 219: 9–15.

    Article  CAS  PubMed  Google Scholar 

  46. Lefebvre A-M, Laville M, Vega N, Riou J, Gaal Lv, Auwerx J, Vidal H . Depot-specific differences in adipose tissue gene expression in lean and obese subjects. Diabetes 1998; 47: 98–103.

    CAS  PubMed  Google Scholar 

  47. Linder K, Arner P, Flores-Morales A, Tollet-Egnell P, Norstedt G . Differentially expressed genes in visceral or subcutaneous adipose tissue of obese men and women. J Lipid Res 2004; 45: 148–154.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    L A Lange, C D Langefeld & L E Wagenknecht

  2. Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO, USA

    J M Norris

  3. Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    B J Nicklas

  4. Diabetes Center, University of California, Los Angeles, Alhambra, CA, 91801, USA

    M F Saad

  5. Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    D W Bowden

Authors
  1. L A Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Norris
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C D Langefeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B J Nicklas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L E Wagenknecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M F Saad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D W Bowden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L A Lange.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lange, L., Norris, J., Langefeld, C. et al. Association of adipose tissue deposition and beta-2 adrenergic receptor variants: the IRAS family study. Int J Obes 29, 449–457 (2005). https://doi.org/10.1038/sj.ijo.0802883

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0802883

Keywords

This article is cited by

Search

Advanced search

Quick links