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 Trp64Arg polymorphism of the β3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity

Abstract

OBJECTIVE: To investigate whether Trp64Arg polymorphism of the β3-adrenergic receptor (β3-AR) gene and Gln223Arg polymorphism of the leptin receptor (Ob-R) gene are associated with obesity in Japanese schoolchildren.

DESIGN: Population study of participants from a rural town located within 50 km northeast of Tokyo based on school medical examinations.

SUBJECTS: 553 Japanese schoolchildren (291 boys and 262 girls) who were 9–15 y old with a mean age of 11.9±1.8 y.

MEASUREMENTS: DNA was extracted from whole blood and genotyped by PCR-RFLP. Height, weight and blood pressure were measured in school medical examinations. Total cholesterol, triglyceride and HDL-cholesterol concentrations were measured by an autoanalyzer. Obesity index, body mass index (BMI) and LDL-cholesterol concentration were calculated by the respective formulae.

RESULTS: In Trp64Arg polymorphism of the β3-AR gene, the number of obese subjects with Trp/Arg or Arg/Arg genotypes was significantly higher than that of the non-obese subjects (χ2=5.79, P=0.02). The obesity index of subjects with the Arg/Arg or Arg/Trp genotype was significantly higher than that of those with the Trp/Trp genotype (8.2±18.7% vs 4.5±15.8%, P=0.04). Moreover, after adjustments for age and gender, BMI of subjects with the Trp/Arg or Arg/Arg genotype was significantly higher than that of those with the Trp/Trp genotype (19.4±3.6 kg/m2 vs 18.9±3.2 kg/m2, P=0.02). However, no significant differences were observed in the clinical characteristics among the genotype groups of the Ob-R gene.

CONCLUSIONS: Trp64Arg polymorphism of the β3-AR gene appears to be a genetic risk factor for obesity in Japanese children, but Gln223Arg polymorphism of the Ob-R gene does not appear to be associated with obesity.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Pi-Sunyer FX . Medical hazards of obesity Ann Intern Med 1993 119: 655–660.

    Article  CAS  Google Scholar 

  2. Hubert HB, Feinleib M, McNamara PM, Castelli WP . Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study Circulation 1983 67: 968–977.

    Article  CAS  Google Scholar 

  3. Reaven GM . Role of insulin resistance in human disease Diabetes 1988 37: 1595–1607.

    Article  CAS  Google Scholar 

  4. Pouliot MC, Després JP, Nadeau A, Moorjani S, Prud'nomme D, Lupien PJ, Tremblay A, Bouchard C. Visceral obesity in men . Associations with glucose tolerance, plasma insulin, and lipoprotein level Diabetes 1992 41: 826–834.

    Article  CAS  Google Scholar 

  5. Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ, Hankinson SE, Hennekens CH, Speizer FE . Body weight and mortality among women New Engl J Med 1995 333: 677–685.

    Article  CAS  Google Scholar 

  6. Whitaker RC, Wright JA, Pepe MS, Seidel KD, Dietz WH . Predicting obesity in young adulthood from childhood and parental obesity New Engl J Med 1997 337: 869–873.

    Article  CAS  Google Scholar 

  7. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH . Long-term morbidity and mortality of overweight adolescents: a follow-up of the Harvard Growth Study of 1922 to 1935 New Engl J Med 1992 327: 1350–1355.

    Article  CAS  Google Scholar 

  8. Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WGH, Boyge V, Howard BV, Bogardus C . Reduced rate of energy expenditure as a risk factor for body-weight gain New Engl J Med 1988 318: 467–472.

    Article  CAS  Google Scholar 

  9. Griffiths M, Payne PR, Stunkard AJ, Rivers JP, Cox M . Metabolic rate and physical development in children at risk of obesity Lancet 1990 336: 76–78.

    Article  CAS  Google Scholar 

  10. Wurmser H, Laessle R, Jacob K, Langhard S, Uhl H, Angst A, Pirke KM . Resting metabolic rate in preadolescent girls at high risk of obesity Int J Obes 1998 22: 793–799.

    Article  CAS  Google Scholar 

  11. Emorine LJ, Marullo S, Briend-Sutren M-M, Patey G, Tate K, Delavier-Klutchko C, Strosberg D . Molecular characterization of the human β3-adrenergic receptor Science 1989 245: 1118–1121.

    Article  CAS  Google Scholar 

  12. Krief S, Lönnqvist F, Raimbault S, Baude B, Spronsen AV, Arner P, Strosberg AD, Ricquier D, Emorine LJ . Tissue distribution β3-adrenergic receptor mRNA in man J Clin Invest 1993 91: 344–349.

    Article  CAS  Google Scholar 

  13. Lönnqvist F, Thörnc A, Nilsell K, Hoffstedt J, Arner P . A pathogenic role of visceral fat β3-adrenoceptors in obesity. J Clin Invest 1995 95: 1109–1116.

    Article  Google Scholar 

  14. Enocksson S, Shimizu M, Lönnqvist F, Nordenström J, Arner P . Demonstration of an in vivo functional β3-adrenoceptor in man J Clin Invest 1995 95: 2239–2245.

    Article  CAS  Google Scholar 

  15. Walston J, Silver K, Bogardus C, Knowler WC, Ccli FS, Austin S, Manning B, Strosberg AD, Stern MP, Raben N, Sorkin JD, Roth J, Shuldiner AR . Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic receptor gene New Engl J Med 1995 333: 343–347.

    Article  CAS  Google Scholar 

  16. Widén E, Lehto M, Kanninen T, Walston J, Shuldiner A, Groop LC . Association of a polymorphism in the β3-adrenergic receptor gene with features of the insulin resistance syndrome in Finns New Engl J Med 1995 333: 348–351.

    Article  Google Scholar 

  17. Clément K, Vaisse C, Manning B S T J, Basdevant A, Guy-Grand B, Ruiz J, Silver KD, Shuldiner AR, Froguel P, Strosberg AD . Genetic variation in the β3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity New Engl J Med 1995 333: 352–354.

    Article  Google Scholar 

  18. Kadowaki H, Yasuda K, Iwamoto K, Otabe S, Shimokawa K, Silver K, Walston J, Yoshinaga H, Kosaka K, Yamada N, Saito Y, Hagura R, Akanuma Y, Shuldiner A, Yazaki Y, Kadowaki T . A mutation in the β3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in the Japanese subject Biochem Biophys Res Commun 1995 215: 555–560.

    Article  CAS  Google Scholar 

  19. Fujisawa T, Ikegami H, Kawaguchi Y, Ogihara T . Meta-analysis of the association of Trp64Arg polymorphism of the β3-adrenergic receptor gene with body mass index J Clin Endocrinol Metab 1998 83: 2441–2444.

    CAS  PubMed  Google Scholar 

  20. Zhang Y, Proenca R, Maffei M, Baronc M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue Nature 1994 372: 425–432.

    Article  CAS  Google Scholar 

  21. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce M, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF . Serum immunoreactive-leptin concentrations in normal-weight and obese humans New Engl J Med 1996 334: 292–295.

    Article  CAS  Google Scholar 

  22. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI . Identification and expression cloning of a leptin receptor, OB-R Cell 1995 83: 1263–1271.

    Article  CAS  Google Scholar 

  23. Tartaglia LA . The leptin receptor J Biol Chem 1997 272: 6093–6096.

    Article  CAS  Google Scholar 

  24. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S . Congenital leptin deficiency is associated with severe early-onset obesity in humans Nature 1997 387: 903–908.

    Article  CAS  Google Scholar 

  25. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougnères P, Lebouc Y, Froguel P, Guy-Grand B . A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction Nature 1998 392: 398–401.

    Article  Google Scholar 

  26. Phillips PH, Lin Q, Hammond HA, Dugan V, Hey PJ, Caskey CJ, Hess JF . Leptin receptor missense mutation in the fatty Zucker rat Nature Genet 1996 13: 18–19.

    Article  CAS  Google Scholar 

  27. Chua SC Jr, White DW, Wu-Peng XS, Okada N, Kershaw EE, Chung WK, Power-Kehoe L, Chua M, Tartaglia LA, Leibel RL . Phenotype of fatty due to Gln269 Pro mutation in the leptin receptor (Lepr) Diabetes 1996 45: 1141–1143.

    Article  Google Scholar 

  28. Considine RV, Considene EL, Williams CJ, Hyde TM, Caro JF . The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations Diabetes 1996 45: 992–994.

    Article  Google Scholar 

  29. Thompson DB, Ravussin E, Bennett PH, Bogardus C . Structure and sequence variation at the human leptin receptor gene in lean and obese Pima Indians Hum Mol Genet 1997 6: 675–679.

    Article  CAS  Google Scholar 

  30. Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T, Azuma N, Natsui K, Nishimura H, Yoshimasa Y, Nishi S, Thompson DB, Nakao K . Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity Diabetologia 1997 40: 1204–1210.

    Article  CAS  Google Scholar 

  31. Murata M, Yamazaki K, Itano M, Inaba M . Standard body weight for height for age between five years and seventeen years Child Health 1980 39: 93–96 (in Japanese).

  32. Friedewald WT, Lexy RJ, Frederickson DS . Estimation of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge Clin Chem 1972 18: 499.

    CAS  Google Scholar 

  33. Sambrook J, Fritsch EF, Maniatis T . Molecular cloning, a laboratory manual 2nd ed. Cold Spring Harbor Laboratory Press: New York 1989 pp 9.16–9.19.

  34. Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, McKeiguc PM, Scott J, Aitman TJ . Leptin receptor gene variation and obesity: lack of association in a white British male population Hum Mol Genet 1997 6: 869–876.

    Article  CAS  Google Scholar 

  35. Fujisawa T, Ikegami H, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Oga T, Ueda H, Shintani M, Fukuda M, Ogihara T . Association of Trp64Arg mutation of the β3-adrenergic receptor with NIDDM and body weight gain Diabetologia 1996 39: 349–352.

    Article  CAS  Google Scholar 

  36. Kurabayashi T, Carcy DGP, Morrison NA . The β3-adrenergic receptor gene Trp64Arg mutation is overrepresented in obese women Diabetes 1996 45: 1358–1363.

    Article  CAS  Google Scholar 

  37. Sakane N, Yoshida T, Umekawa T, Kondo M, Sakai Y, Takahashi T . β3-adrenergic receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome Diabetologia 1997 40: 200–204.

    Article  CAS  Google Scholar 

  38. Ueda K, Tanizawa Y, Oota Y, Inoue H, Kizuki N, Inoue H, Tsukuda K, Asano T, Oka Y . Prevalence of the Trp64Arg missense mutation of the β3-adrenergic receptor gene in Japanese subjects Metabolism 1997 46: 199–202.

    Article  CAS  Google Scholar 

  39. Azuma N, Yoshimasa Y, Nishimura H, Yamamoto Y, Masuzaki H, Suga J, Shigemoto M, Matsuoka N, Tanaka T, Satoh N, Igaki T, Miyamoto Y, Itoh H, Yoshimasa T, Hosoda K, Nishi S, Nakao K . The significant of the Trp64Arg mutation of the β3-adrenergic receptor gene and insulin resistance in Japanese subjects Metabolism 1998 47: 456–460.

    Article  CAS  Google Scholar 

  40. Sun L, Ishibashi S, Osuga J, Harada K, Ohashi K, Gotoda T, Fukuo Y, Yazaki Y, Yamada N . Clinical features associated with the homozygous Trp64Arg mutation of the β3-adrenergic receptor: no evidence for its association with obesity in Japanese Arterioscler Thromb Vasc Biol 1998 18: 941–946.

    Article  CAS  Google Scholar 

  41. Li LS, Lönnqvist F, Luthman H, Arner P . Phenotypic characterization of the Trp64Arg polymorphism in the beta3-adrenergic receptor gene in normal weight and obese subjects Diabetologia 1996 39: 857–860.

    Article  CAS  Google Scholar 

  42. Gagnon J, Mauriége P, Roy S, Sjöström D, Chagnon YC, Dionne FT, Oppert JM, Pérusse L, Sjöström L, Bouchard . The Trp64Arg mutation of the β3-adrenergic receptor gene has no effect on obesity phenotypes in the Québec Family Study and obese subjects cohorts J Clin Invest 1996 98: 2086–2093.

    Article  CAS  Google Scholar 

  43. Hinney A, Lentes K-U, Rosenkranz K, Barth N, Roth H, Ziegler A, Hennighausen K, Coners H, Wurmser H, Jacob K, Römer G, Winnikes U, Mayer H, Herzog W, Lehmkuhl G, Poustka F, Schmidt MH, Blum WF, Prike KM, Schäfer H, Grzcschik K-H, Remschmidt H, Hebebrand J . β3-adrenergic-receptor allele distribution in children, adolescents and young adults with obesity, underweight or anorexia nervosa Int J Obes 1997 21: 224–230.

    Article  CAS  Google Scholar 

  44. Rissanen J, Kuopusjärvi M, Pihlajamäinen R, Heikkinen S, Vanhala M, Kckäläinen P, Kuusisto J, Laakso M . The Trp64Arg polymorphism of the β3-adrenergic-receptor gene; lack of association with NIDDM and features of insulin resistance syndrome Diabetes Care 1997 20: 1319–1323.

    Article  CAS  Google Scholar 

  45. Anderson NMcF, Bannett F, Wilks R, Howell S, Newsome C, Cruickshank K, Forrester T . The Trp64Arg mutation of the β3-adrenergic-receptor is associated with hyperglycemia and current body mass index in Jamaican women Metabolism 1998 47: 617–621.

    Article  Google Scholar 

  46. Himes JH, Dietz WH . Guidelines for overweight in adolescent preventive services: recommendations from an expert committee Am J Clin Nutr 1994 59: 307–316.

    Article  CAS  Google Scholar 

  47. Tokunaga K, Ishikawa K, Sudo H, Matsuzawa Y, Yamamoto A, Tarui S . Serum lipoprotein profile in Japanese obese children Int J Obes 1982 6: 399–404.

    CAS  PubMed  Google Scholar 

  48. Yanagi H, Hamaguchi H, Hirano C, Shimakura Y, Takita H, Tsuchiya S, Yoshiwara C . Hyperlipidemia, hypoalphalipoproteinemia and liver dysfunction in Japanese school-age children with obesity Jap J Public Health 1992 40: 1021–1017 (in Japanese).

    Google Scholar 

  49. Piétri-Rouxel F, Mannimg BStJ, Gros J, Strosbcrg AD . The biochemical effect of the naturally occurring Trp64→Arg mutation on human β3-adrenoceptor activity Eur J Biochem 1997 247: 1174–1179.

    Article  Google Scholar 

  50. Umekawa T, Yoshida T, Sakane N, Kogure A, Kondo M, Honjyo H . Trp64Arg mutation of β3-adrenoceptor gene deteriorates lipolysis induced by β3-adrenoceptor agonist in human omental adipocytes Diabetes 1999 48: 117–120.

    Article  CAS  Google Scholar 

  51. Echwald SM, Sorensen TD, Sorensen TIA, Hansen AT, Andersen T, Chung WK, Leibel RL, Pedersen O . Amino acid variants in the human leptin rcceptor: lack of association to juvenile onset obesity Biochem Biophys Res Commun 1997 233: 248–252.

    Article  CAS  Google Scholar 

  52. Silver K, Walston J, Chung WK, Yao F, Parikh VV, Andersen R, Cheskin LJ, Elahi D, Muller D, Leibel RL, Shuldiner AR . The Gln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate with traits related to obesity Diabetes 1997 46: 1898–1900.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant for scientific research from the Ministry of Education (09772047, 11770191).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Endo, K., Yanagi, H., Hirano, C. et al. Association of Trp64Arg polymorphism of the β3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity. Int J Obes 24, 443–449 (2000). https://doi.org/10.1038/sj.ijo.0801177

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0801177

Keywords

This article is cited by

Search

Quick links