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Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation

International Journal of Obesity volume 31, pages 813–819 (2007)Cite this article

Abstract

Background and aims:

Obesity is associated with a blunted β-adrenoceptor-mediated lipolysis and fat oxidation. We investigated whether polymorphisms in codon 16, 27 and 164 of the β2-adrenoceptor gene (ADRB2) and exon 10 of the G protein β3-subunit gene (GNB3) are associated with alterations in in vivo lipolysis and fat oxidation.

Design and methods:

Sixty-five male and 43 female overweight and obese subjects (body mass index (BMI) range: 26.1–48.4 kg/m2) were included. Energy expenditure (EE), respiratory quotient (RQ), circulating free fatty acid (FFA) and glycerol levels were determined after stepwise infusion of increasing doses of the non-selective β-agonist isoprenaline (ISO).

Results:

In women, the Arg16 allele of the ADRB2 gene was associated with a blunted increase in circulating FFA, glycerol and a decreased fat oxidation during ISO stimulation. In men, the Arg16 allele was significantly associated with a blunted increase in FFA but not in glycerol or fat oxidation.

Conclusion:

These results suggest that genetic variation in the ADRB2 gene is associated with disturbances in in vivo β-adrenoceptor-mediated lipolysis and fat oxidation during β-adrenergic stimulation in overweight and obese subjects; these effects are influenced by gene–gender interactions.

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References

  1. Blaak EE, Van Baak MA, Kemerink GJ, Pakbiers MT, Heidendal GA, Saris WH . Beta-adrenergic stimulation of skeletal muscle metabolism in relation to weight reduction in obese men. Am J Physiol 1994; 267 (2 Part 1): E316–E322.

    CAS  PubMed  Google Scholar 

  2. Blaak EE, Saris WH, Wolffenbuttel BH . Substrate utilization and thermogenic responses to beta-adrenergic stimulation in obese subjects with NIDDM. Int J Obes Relat Metab Disord 1999; 23: 411–418.

    Article  CAS  Google Scholar 

  3. Blaak EE, van Aggel-Leijssen DP, Wagenmakers AJ, Saris WH, van Baak MA . Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise. Diabetes 2000; 49: 2102–2107.

    Article  CAS  Google Scholar 

  4. Blaak EE, Van Baak MA, Kemerink GJ, Pakbiers MT, Heidendal GA, Saris WH . Beta-adrenergic stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men. Am J Physiol 1994; 267 (2 Part 1): E306–E315.

    CAS  PubMed  Google Scholar 

  5. Schiffelers SL, Blaak EE, Baarends EM, Van Baak MA, Saris WH, Wouters EF et al. Beta-adrenoceptor-mediated thermogenesis and lipolysis in patients with chronic obstructive pulmonary disease. Am J Physiol Endocrinol Metab 2001; 280: E357–E364.

    Article  CAS  Google Scholar 

  6. Reynisdottir S, Wahrenberg H, Carlstrom K, Rossner S, Arner P . Catecholamine resistance in fat cells of women with upper body obesity due to decreased expression of beta 2-adrenoceptors. Diabetologia 1994; 37: 428–435.

    Article  CAS  Google Scholar 

  7. Kobilka BK, MacGregor C, Daniel K, Kobilka TS, Caron MG, Lefkowitz RJ . Functional activity and regulation of human beta 2-adrenergic receptors expressed in Xenopus oocytes. J Biol Chem 1987; 262: 15796–15802.

    CAS  PubMed  Google Scholar 

  8. Kobilka BK, Frielle T, Dohlman HG, Bolanowski MA, Dixon RA, Keller P et al. Delineation of the intronless nature of the genes for the human and hamster beta 2-adrenergic receptor and their putative promoter regions. J Biol Chem 1987; 262: 7321–7327.

    CAS  PubMed  Google Scholar 

  9. Liggett SB . Pharmacogenetics of beta-1- and beta-2-adrenergic receptors. Pharmacology 2000; 61: 167–173.

    Article  CAS  Google Scholar 

  10. Leineweber K, Brodde OE . Beta2-adrenoceptor polymorphisms: relation between in vitro and in vivo phenotypes. Life Sci 2004; 74: 2803–2814.

    Article  CAS  Google Scholar 

  11. Green SA, Turki J, Innis M, Liggett SB . Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9419.

    Article  CAS  Google Scholar 

  12. Bengtsson K, Orho-Melander M, Melander O, Lindblad U, Ranstam J, Rastam L et al. Beta(2)-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes. Hypertension 2001; 37: 1303–1308.

    Article  CAS  Google Scholar 

  13. Kim SH, Kim DJ, Seo IA, Min YK, Lee MS, Kim KW et al. Significance of beta2-adrenergic receptor gene polymorphism in obesity and type 2 diabetes mellitus in Korean subjects. Metabolism 2002; 51: 833–837.

    Article  CAS  Google Scholar 

  14. Iwamoto N, Ogawa Y, Kajihara S, Hisatomi A, Yasutake T, Yoshimura T et al. Gln27Glu beta2-adrenergic receptor variant is associated with hypertriglyceridemia and the development of fatty liver. Clin Chim Acta 2001; 314: 85–91.

    Article  CAS  Google Scholar 

  15. Ukkola O, Rankinen T, Weisnagel SJ, Sun G, Perusse L, Chagnon YC et al. Interactions among the alpha2-, beta2-, and beta3-adrenergic receptor genes and obesity-related phenotypes in the Quebec family study. Metabolism 2000; 49: 1063–1070.

    Article  CAS  Google Scholar 

  16. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L et al. 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  Google Scholar 

  17. Hellstrom L, Large V, Reynisdottir S, Wahrenberg H, Arner P . The different effects of a Gln27Glu beta 2-adrenoceptor gene polymorphism on obesity in males and in females. J Intern Med 1999; 245: 253–259.

    Article  CAS  Google Scholar 

  18. Meirhaeghe A, Helbecque N, Cottel D, Amouyel P . Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population. Int J Obes Relat Metab Disord 2000; 24: 382–387.

    Article  CAS  Google Scholar 

  19. Meirhaeghe A, Helbecque N, Cottel D, Amouyel P . Beta2-adrenoceptor gene polymorphism, body weight, and physical activity. Lancet 1999; 353: 896.

    Article  CAS  Google Scholar 

  20. Mori Y, Kim-Motoyama H, Ito Y, Katakura T, Yasuda K, Ishiyama-Shigemoto S et al. The Gln27Glu beta2-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  Google Scholar 

  21. Ishiyama-Shigemoto S, Yamada K, Yuan X, Ichikawa F, Nonaka K . Association of polymorphisms in the beta2-adrenergic receptor gene with obesity, hypertriglyceridaemia, and diabetes mellitus. Diabetologia 1999; 42: 98–101.

    Article  CAS  Google Scholar 

  22. Oomen JM, van Rossum CT, Hoebee B, Saris WH, van Baak MA . Beta2-adrenergic receptor polymorphisms and salbutamol-stimulated energy expenditure. J Clin Endocrinol Metab 2005; 90: 2301–2307.

    Article  CAS  Google Scholar 

  23. Green SA, Cole G, Jacinto M, Innis M, Liggett SB . A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 1993; 268: 23116–23121.

    CAS  PubMed  Google Scholar 

  24. Green SA, Rathz DA, Schuster AJ, Liggett SB . The Ile164 beta(2)-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to G(s). Eur J Pharmacol 2001; 421: 141–147.

    Article  CAS  Google Scholar 

  25. Hoffstedt J, Iliadou A, Pedersen NL, Schalling M, Arner P . The effect of the beta(2) adrenoceptor gene Thr164Ile polymorphism on human adipose tissue lipolytic function. Br J Pharmacol 2001; 133: 708–712.

    Article  CAS  Google Scholar 

  26. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R et al. Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet 1998; 18: 45–48.

    Article  CAS  Google Scholar 

  27. Patten JL, Johns DR, Valle D, Eil C, Gruppuso PA, Steele G et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. N Engl J Med 1990; 322: 1412–1419.

    Article  CAS  Google Scholar 

  28. Carel JC, Le Stunff C, Condamine L, Mallet E, Chaussain JL, Adnot P et al. Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency. J Clin Endocrinol Metab 1999; 84: 4127–4131.

    Article  CAS  Google Scholar 

  29. Schunkert H, Hense HW, Doring A, Riegger GA, Siffert W . Association between a polymorphism in the G protein beta3 subunit gene and lower renin and elevated diastolic blood pressure levels. Hypertension 1998; 32: 510–513.

    Article  CAS  Google Scholar 

  30. Benjafield AV, Jeyasingam CL, Nyholt DR, Griffiths LR, Morris BJ . G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension. Hypertension 1998; 32: 1094–1097.

    Article  CAS  Google Scholar 

  31. Siffert W, Forster P, Jockel KH, Mvere DA, Brinkmann B, Naber C et al. Worldwide ethnic distribution of the G protein beta3 subunit 825 T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. J Am Soc Nephrol 1999; 10: 1921–1930.

    CAS  Google Scholar 

  32. Dong Y, Zhu H, Wang X, Dalageorgou C, Carter N, Spector TD et al. Obesity reveals an association between blood pressure and the G-protein beta3-subunit gene: a study of female dizygotic twins. Pharmacogenetics 2004; 14: 419–427.

    Article  CAS  Google Scholar 

  33. Hauner H, Meier M, Jockel KH, Frey UH, Siffert W . Prediction of successful weight reduction under sibutramine therapy through genotyping of the G-protein beta3 subunit gene (GNB3) C825T polymorphism. Pharmacogenetics 2003; 13: 453–459.

    Article  CAS  Google Scholar 

  34. Hegele RA, Anderson C, Young TK, Connelly PW . G-protein beta3 subunit gene splice variant and body fat distribution in Nunavut Inuit. Genome Res 1999; 9: 972–977.

    Article  CAS  Google Scholar 

  35. Ryden M, Faulds G, Hoffstedt J, Wennlund A, Arner P . Effect of the (C825T) Gbeta(3) polymorphism on adrenoceptor-mediated lipolysis in human fat cells. Diabetes 2002; 51: 1601–1608.

    Article  CAS  Google Scholar 

  36. Siri WE . The gross composition of the body. Adv Biol Med Phys 1956; 4: 239–280.

    Article  CAS  Google Scholar 

  37. Devlin B, Risch N . A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 1995; 29: 311–322.

    Article  CAS  Google Scholar 

  38. Eriksson P, Dahlman I, Ryden M, Hoffstedt J, Arner P . Relationship between beta-2 adrenoceptor gene haplotypes and adipocyte lipolysis in women. Int J Obes Relat Metab Disord 2004; 28: 185–190.

    Article  CAS  Google Scholar 

  39. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000; 97: 10483–10488.

    Article  CAS  Google Scholar 

  40. Schaid DJ, Jacobsen SJ . Biased tests of association: comparisons of allele frequencies when departing from Hardy–Weinberg proportions. Am J Epidemiol 1999; 149: 706–711.

    Article  CAS  Google Scholar 

  41. Blaak EE, van Baak MA, Saris WH . Beta-adrenergically stimulated fat oxidation is diminished in middle-aged compared to young subjects. J Clin Endocrinol Metab 1999; 84: 3764–3769.

    CAS  PubMed  Google Scholar 

  42. Kanaley JA, Cryer PE, Jensen MD . Fatty acid kinetic responses to exercise. Effects of obesity, body fat distribution, and energy-restricted diet. J Clin Invest 1993; 92: 255–261.

    Article  CAS  Google Scholar 

  43. Blaak E . Gender differences in fat metabolism. Curr Opin Clin Nutr Metab Care 2001; 4: 499–502.

    Article  CAS  Google Scholar 

  44. Arner P . Catecholamine-induced lipolysis in obesity. Int J Obes Relat Metab Disord 1999; 23 (Suppl 1): 10–13.

    Article  Google Scholar 

  45. Blaak EE, Schiffelers SL, Saris WH, Mensink M, Kooi ME . Impaired beta-adrenergically mediated lipolysis in skeletal muscle of obese subjects. Diabetologia 2004; 47: 1462–1468.

    Article  CAS  Google Scholar 

  46. Dallongeville J, Helbecque N, Cottel D, Amouyel P, Meirhaeghe A . The Gly16—>Arg16 and Gln27—>Glu27 polymorphisms of beta2-adrenergic receptor are associated with metabolic syndrome in men. J Clin Endocrinol Metab 2003; 88: 4862–4866.

    Article  CAS  Google Scholar 

  47. Hagstrom-Toft E, Bolinder J, Ungerstedt U, Arner P . A circadian rhythm in lipid mobilization which is altered in IDDM. Diabetologia 1997; 40: 1070–1078.

    Article  CAS  Google Scholar 

  48. Bruck H, Leineweber K, Buscher R, Ulrich A, Radke J, Insel PA et al. The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo. Pharmacogenetics 2003; 13: 59–66.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by a research grant from The Netherlands Association for Scientific Research (NWO) to EE Blaak and Swedish Research Council to P Arner.

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Authors and Affiliations

  1. Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    J W E Jocken, E E Blaak, S Schiffelers, M A van Baak & W H M Saris

  2. Department of Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

    P Arner

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  1. J W E Jocken
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  2. E E Blaak
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Correspondence to J W E Jocken.

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Jocken, J., Blaak, E., Schiffelers, S. et al. Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation. Int J Obes 31, 813–819 (2007). https://doi.org/10.1038/sj.ijo.0803499

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