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.

  • Original Article
  • Published:

UCP2 A55V variant is associated with obesity and related phenotypes in an aboriginal community in Taiwan

Abstract

Objective:

Human uncoupling proteins 2 and 3 (UCP2 and UCP3) are two mitochondrial proteins that are involved in the control of metabolism of fatty acid and possibly protect against oxidative damage. The aim of this study was to analyze genetic associations of four polymorphisms of the UCP2 and UCP3 genes with insulin, leptin concentration and obesity in Taiwan aborigines.

Research methods:

Four polymorphisms were compared in 324 obese (body mass index (BMI) 30 kg/m2) and overweight (30>BMI 25 kg/m2) subjects, and 114 normal weight subjects (BMI <25 kg/m2) in an aboriginal community of southern Taiwan. Anthropometric characteristics and fasting levels of insulin, leptin, triglycerides and cholesterol were measured.

Results:

Before and after adjusting for age distribution, only the Val55 allele in exon 4 of the UCP2 gene increased the risk of overweight and obesity (adjusted odds ratio (OR)=2.02, P=0.004) in comparison with Ala55. UCP2 V55V is also associated with higher fasting insulin levels than A55V (P=0.01) and A55A (P=0.04) in the obese/overweight group. Using the COCAPHASE program of the UNPHASED software, haplotype analysis of three single nucleotide polymorphisms (A55V-G866A-C-55T) revealed that A-G-C (73% in obese subjects and 77% in controls) was the most common haplotype and that the haplotype V-A-T (13% in obese subjects and 5% in controls) was significantly increased in obese and overweight subjects (BMI 25 kg/m2) (OR=2.62, P<0.001).

Discussions:

UCP2 A55V variant might predispose to obesity and Val55 allele to confer population-attributable risk for 9.5% of obese disorders and increase insulin concentrations. The V-A-T haplotype within UCP2-UCP3 gene cluster is also significantly associated with obesity in Paiwan aborigines.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Wolkow CA, Iser WB . Uncoupling protein homologs may provide a link between mitochondria, metabolism and lifespan. Ageing Res Rev 2006; 5: 196–208.

    Article  CAS  Google Scholar 

  2. Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM . The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 2004; 55: 576–580.

    Article  CAS  Google Scholar 

  3. Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F et al. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet 2001; 28: 178–183.

    Article  CAS  Google Scholar 

  4. Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997; 15: 269–272.

    Article  CAS  Google Scholar 

  5. Vidal-Puig A, Solanes G, Grujic D, Flier JS, Lowell BB . UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun 1997; 235: 79–82.

    Article  CAS  Google Scholar 

  6. Oberkofler H, Liu YM, Esterbauer H, Hell E, Krempler F, Patsch W . Uncoupling protein-2 gene: reduced mRNA expression in intraperitoneal adipose tissue of obese humans. Diabetologia 1998; 41: 940–946.

    Article  CAS  Google Scholar 

  7. Chan CB, De Leo D, Joseph JW, McQuaid TS, Ha XF, Xu F et al. Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 2001; 50: 1302–1310.

    Article  CAS  Google Scholar 

  8. Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 2001; 105: 745–755.

    Article  CAS  Google Scholar 

  9. Harper ME, Dent R, Monemdjou S, Bezaire V, Van Wyck L, Wells G et al. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women. Diabetes 2002; 51: 2459–2466.

    Article  CAS  Google Scholar 

  10. Pratley RE, Thompson DB, Prochazka M, Baier L, Mott D, Ravussin E et al. An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest 1998; 101: 1757–1764.

    Article  CAS  Google Scholar 

  11. Millet L, Vidal H, Andreelli F, Larrouy D, Riou JP, Ricquier D et al. Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. J Clin Invest 1997; 100: 2665–2670.

    Article  CAS  Google Scholar 

  12. Walder K, Norman RA, Hanson RL, Schrauwen P, Neverova M, Jenkinson CP et al. Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians. Hum Mol Genet 1998; 7: 1431–1435.

    Article  CAS  Google Scholar 

  13. Bouchard C, Perusse L, Chagnon YC, Warden C, Ricquier D . Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans. Hum Mol Genet 1997; 6: 1887–1889.

    Article  CAS  Google Scholar 

  14. Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K et al. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002; 51: 3331–3335.

    Article  CAS  Google Scholar 

  15. Buemann B, Schierning B, Toubro S, Bibby BM, Sorensen T, Dalgaard L et al. The association between the val/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency. Int J Obes Relat Metab Disord 2001; 25: 467–471.

    Article  CAS  Google Scholar 

  16. Astrup A, Toubro S, Dalgaard LT, Urhammer SA, Sorensen TI, Pedersen O . Impact of the v/v 55 polymorphism of the uncoupling protein 2 gene on 24-h energy expenditure and substrate oxidation. Int J Obes Relat Metab Disord 1999; 23: 1030–1034.

    Article  CAS  Google Scholar 

  17. Cassell PG, Saker PJ, Huxtable SJ, Kousta E, Jackson AE, Hattersley AT et al. Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin. Diabetologia 2000; 43: 1558–1564.

    Article  CAS  Google Scholar 

  18. Otabe S, Clement K, Dina C, Pelloux V, Guy-Grand B, Froguel P et al. A genetic variation in the 5′ flanking region of the UCP3 gene is associated with body mass index in humans in interaction with physical activity. Diabetologia 2000; 43: 245–249.

    Article  CAS  Google Scholar 

  19. Herrmann SM, Wang JG, Staessen JA, Kertmen E, Schmidt-Petersen K, Zidek W et al. Uncoupling protein 1 and 3 polymorphisms are associated with waist-to-hip ratio. J Mol Med 2003; 81: 327–332.

    Article  Google Scholar 

  20. Yanovski JA, Diament AL, Sovik KN, Nguyen TT, Li H, Sebring NG et al. Associations between uncoupling protein 2, body composition, and resting energy expenditure in lean and obese African American, white, and Asian children. Am J Clin Nutr 2000; 71: 1405–1420.

    Article  CAS  Google Scholar 

  21. D'Adamo M, Perego L, Cardellini M, Marini MA, Frontoni S, Andreozzi F et al. The −866A/A genotype in the promoter of the human uncoupling protein 2 gene is associated with insulin resistance and increased risk of type 2 diabetes. Diabetes 2004; 53: 1905–1910.

    Article  CAS  Google Scholar 

  22. Kubota T, Mori H, Tamori Y, Okazawa H, Fukuda T, Miki M et al. Molecular screening of uncoupling protein 2 gene in patients with noninsulin-dependent diabetes mellitus or obesity. J Clin Endocrinol Metab 1998; 83: 2800–2804.

    CAS  PubMed  Google Scholar 

  23. Shiinoki T, Suehiro T, Ikeda Y, Inoue M, Nakamura T, Kumon Y et al. Screening for variants of the uncoupling protein 2 gene in Japanese patients with non-insulin-dependent diabetes mellitus. Metabolism 1999; 48: 581–584.

    Article  CAS  Google Scholar 

  24. Tu N, Chen H, Winnikes U, Reinert I, Marmann G, Pirke KM et al. Structural organization and mutational analysis of the human uncoupling protein-2 (hUCP2) gene. Life Sci 1999; 64: PL41–PL50.

    CAS  PubMed  Google Scholar 

  25. Dalgaard LT, Sorensen TI, Andersen T, Hansen T, Pedersen O . An untranslated insertion variant in the uncoupling protein 2 gene is not related to body mass index and changes in body weight during a 26-year follow-up in Danish Caucasian men. Diabetologia 1999; 42: 1413–1416.

    Article  CAS  Google Scholar 

  26. Otabe S, Clement K, Rich N, Warden C, Pecqueur C, Neverova M et al. Mutation screening of the human UCP 2 gene in normoglycemic and NIDDM morbidly obese patients: lack of association between new UCP 2 polymorphisms and obesity in French Caucasians. Diabetes 1998; 47: 840–842.

    Article  CAS  Google Scholar 

  27. Mancini FP, Sabatino L, Colantuoni V, Pasanisi F, Finelli C, Contaldo F et al. Variants of uncoupling protein-2 gene and obesity: interaction with peroxisome proliferator-activated receptorgamma2. Clin Endocrinol (Oxford) 2003; 59: 817–822.

    Article  CAS  Google Scholar 

  28. Wang TN, Huang MC, Chang WT, Ko AM, Tsai EM, Liu CS et al. G-2548A polymorphism of the leptin gene is correlated with extreme obesity in Taiwanese aborigines. Obesity (Silver Spring) 2006; 14: 183–187.

    Article  CAS  Google Scholar 

  29. Sesti G, Cardellini M, Marini MA, Frontoni S, D'Adamo M, Del Guerra S et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003; 52: 1280–1283.

    Article  CAS  Google Scholar 

  30. Fallin D, Schork NJ . Accuracy of haplotype frequency estimation for biallelic loci, via the expectation-maximization algorithm for unphased diploid genotype data. Am J Hum Genet 2000; 67: 947–959.

    Article  CAS  Google Scholar 

  31. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.

    Article  Google Scholar 

  32. Yu X, Jacobs Jr DR, Schreiner PJ, Gross MD, Steffes MW, Fornage M . The uncoupling protein 2Ala55Val polymorphism is associated with diabetes mellitus: the CARDIA study. Clin Chem 2005; 51: 1451–1456.

    Article  CAS  Google Scholar 

  33. Cusin I, Zakrzewska KE, Boss O, Muzzin P, Giacobino JP, Ricquier D et al. Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins. Diabetes 1998; 47: 1014–1019.

    Article  CAS  Google Scholar 

  34. Combatsiaris TP, Charron MJ . Downregulation of uncoupling protein 2 mRNA in white adipose tissue and uncoupling protein 3 mRNA in skeletal muscle during the early stages of leptin treatment. Diabetes 1999; 48: 128–133.

    Article  CAS  Google Scholar 

  35. Zhou YT, Shimabukuro M, Koyama K, Lee Y, Wang MY, Trieu F et al. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc Natl Acad Sci USA 1997; 94: 6386–6390.

    Article  CAS  Google Scholar 

  36. Ukkola O, Tremblay A, Sun G, Chagnon YC, Bouchard C . Genetic variation at the uncoupling protein 1, 2 and 3 loci and the response to long-term overfeeding. Eur J Clin Nutr 2001; 55: 1008–1015.

    Article  CAS  Google Scholar 

  37. van Rossum CT, Hoebee B, Seidell JC, Bouchard C, van Baak MA, de Groot CP et al. Genetic factors as predictors of weight gain in young adult Dutch men and women. Int J Obes Relat Metab Disord 2002; 26: 517–528.

    Article  CAS  Google Scholar 

  38. Kimm SY, Glynn NW, Aston CE, Damcott CM, Poehlman ET, Daniels SR et al. Racial differences in the relation between uncoupling protein genes and resting energy expenditure. Am J Clin Nutr 2002; 75: 714–719.

    Article  CAS  Google Scholar 

  39. Sweeney C, Murtaugh MA, Baumgartner KB, Byers T, Giuliano AR, Herrick JS et al. Insulin-like growth factor pathway polymorphisms associated with body size in Hispanic and non-Hispanic white women. Cancer Epidemiol Biomarkers Prev 2005; 14: 1802–1809.

    Article  CAS  Google Scholar 

  40. Diamond JM . Taiwan's gift to the world. Nature 2000; 403: 709–710.

    Article  CAS  Google Scholar 

  41. Cheng LS, Chiang SL, Tu HP, Chang SJ, Wang TN, Ko AM et al. Genomewide scan for gout in Taiwanese aborigines reveals linkage to chromosome 4q25. Am J Hum Genet 2004; 75: 498–503.

    Article  CAS  Google Scholar 

  42. Wang WH, Chang SJ, Wang TN, Cheng LSC, Feng YP, Chen CJ et al. Complex segregation and linkage analysis of familial gout in taiwanese aborigines. Arthritis Rheum 2004; 50: 242–246.

    Article  CAS  Google Scholar 

  43. Wang H, Chu WS, Lu T, Hasstedt SJ, Kern PA, Elbein SC . Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004; 286: E1–E7.

    Article  CAS  Google Scholar 

  44. Hesselink MK, Mensink M, Schrauwen P . Human uncoupling protein-3 and obesity: an update. Obes Res 2003; 11: 1429–1443.

    Article  CAS  Google Scholar 

  45. Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM, Bouillaud F et al. The biology of mitochondrial uncoupling proteins. Diabetes 2004; 53 (Suppl 1): S130–S135.

    Article  CAS  Google Scholar 

  46. Silverman EK, Palmer LJ . Case–control association studies for the genetics of complex respiratory diseases. Am J Respir Cell Mol Biol 2000; 22: 645–648.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Health Research Institute (NHRI-EX90-8803PL), Kaohsiung Medical University (KMU92-Q-01) and the National Science Council (NSC 92-2320-B-037-037), Taiwan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Y C Ko.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, T., Huang, M., Lin, H. et al. UCP2 A55V variant is associated with obesity and related phenotypes in an aboriginal community in Taiwan. Int J Obes 31, 1746–1752 (2007). https://doi.org/10.1038/sj.ijo.0803648

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803648

Keywords

This article is cited by

Search

Quick links