Table of Contents Author Guidelines Submit a Manuscript
Journal of Obesity
Volume 2011, Article ID 340241, 12 pages
http://dx.doi.org/10.1155/2011/340241
Review Article

Genetic Variance in Uncoupling Protein 2 in Relation to Obesity, Type 2 Diabetes, and Related Metabolic Traits: Focus on the Functional −866G>A Promoter Variant (rs659366)

Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, 4000 Roskilde, Denmark

Received 1 December 2010; Accepted 21 February 2011

Academic Editor: R. Prager

Copyright © 2011 Louise T. Dalgaard. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. R. E. Gimeno, M. Dembski, X. Weng et al., “Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis,” Diabetes, vol. 46, no. 5, pp. 900–906, 1997. View at Google Scholar · View at Scopus
  2. C. Fleury, M. Neverova, S. Collins et al., “Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia,” Nature Genetics, vol. 15, no. 3, pp. 269–272, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. O. Boss, S. Samec, A. Paoloni-Giacobino et al., “Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression,” FEBS Letters, vol. 408, no. 1, pp. 39–42, 1997. View at Publisher · View at Google Scholar · View at Scopus
  4. B. B. Lowell, “Uncoupling protein-3 (UCP3): a mitochondrial carrier in search of a function,” International Journal of Obesity, vol. 23, supplement 6, pp. S43–S45, 1999. View at Google Scholar · View at Scopus
  5. D. Sanchis, C. Fleury, N. Chomiki et al., “BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast,” Journal of Biological Chemistry, vol. 273, no. 51, pp. 34611–34615, 1998. View at Publisher · View at Google Scholar · View at Scopus
  6. X. X. Yu, W. Mao, A. Zhong et al., “Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation,” FASEB Journal, vol. 14, no. 11, pp. 1611–1618, 2000. View at Google Scholar · View at Scopus
  7. W. Mao, X. X. Yu, A. Zhong et al., “UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells,” FEBS Letters, vol. 443, no. 3, pp. 326–330, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. V. Golozoubova, B. Cannon, and J. Nedergaard, “UCP1 is essential for adaptive adrenergic nonshivering thermogenesis,” American Journal of Physiology, vol. 291, no. 2, pp. E350–E357, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. V. Golozoubova, E. Hohtola, A. Matthias, A. Jacobsson, B. Cannon, and J. Nedergaard, “Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold,” The FASEB Journal, vol. 15, no. 11, pp. 2048–2050, 2001. View at Google Scholar · View at Scopus
  10. A. Vidal-Puig, G. Solanes, D. Grujic, J. S. Flier, and B. B. Lowell, “UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue,” Biochemical and Biophysical Research Communications, vol. 235, no. 1, pp. 79–82, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. S. Samec, J. Seydoux, and A. G. Dulloo, “Post-starvation gene expression of skeletal muscle uncoupling protein 2 and uncoupling protein 3 in response to dietary fat levels and fatty acid composition: a link with insulin resistance,” Diabetes, vol. 48, no. 2, pp. 436–441, 1999. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Samec, J. Seydoux, and A. G. Dulloo, “Skeletal muscle UCP3 and UCP2 gene expression in response to inhibition of free fatty acid flux through mitochondrial β-oxidation,” Pflugers Archiv European Journal of Physiology, vol. 438, no. 4, pp. 452–457, 1999. View at Publisher · View at Google Scholar · View at Scopus
  13. H. Kageyama, A. Suga, M. Kashiba et al., “Increased uncoupling protein-2 and -3 gene expressions in skeletal muscle of STZ-induced diabetic rats,” FEBS Letters, vol. 440, no. 3, pp. 450–453, 1998. View at Publisher · View at Google Scholar · View at Scopus
  14. J. E. P. Brown, S. Thomas, J. E. Digby, and S. J. Dunmore, “Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets,” FEBS Letters, vol. 513, no. 2-3, pp. 189–192, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. D. W. Gong, Y. He, M. Karas, and M. Reitman, “Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, β3-adrenergic agonists, and leptin,” Journal of Biological Chemistry, vol. 272, no. 39, pp. 24129–24132, 1997. View at Publisher · View at Google Scholar · View at Scopus
  16. J. Matsuda, K. Hosoda, H. Itoh et al., “Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their gene expression in rats fed high-fat diet,” FEBS Letters, vol. 418, no. 1-2, pp. 200–204, 1997. View at Publisher · View at Google Scholar · View at Scopus
  17. O. Boss, S. Samec, F. Kühne et al., “Uncoupling protein-3 expression in rodent skeletal muscle is modulated by food intake but not by changes in environmental temperature,” Journal of Biological Chemistry, vol. 273, no. 1, pp. 5–8, 1998. View at Publisher · View at Google Scholar · View at Scopus
  18. M. D. Brand and T. C. Esteves, “Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3,” Cell Metabolism, vol. 2, no. 2, pp. 85–93, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. S. Cadenas, J. A. Buckingham, S. Samec et al., “UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged,” FEBS Letters, vol. 462, no. 3, pp. 257–260, 1999. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Cadenas, K. S. Echtay, J. A. Harper et al., “The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3,” Journal of Biological Chemistry, vol. 277, no. 4, pp. 2773–2778, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. K. S. Echtay, D. Roussel, J. St-Plerre et al., “Superoxide activates mitochondrial uncoupling proteins,” Nature, vol. 415, no. 6867, pp. 96–99, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. K. S. Echtay, E. Winkler, K. Frischmuth, and M. Klingenberg, “Uncoupling proteins 2 and 3 are highly active H(+) transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone),” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 4, pp. 1416–1421, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. M. Jabůrek, M. Vařecha, R. E. Gimeno et al., “Transport function and regulation of mitochondrial uncoupling proteins 2 and 3,” Journal of Biological Chemistry, vol. 274, no. 37, pp. 26003–26007, 1999. View at Publisher · View at Google Scholar · View at Scopus
  24. K. S. Echtay, T. C. Esteves, J. L. Pakay et al., “A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling,” EMBO Journal, vol. 22, no. 16, pp. 4103–4110, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. M. P. Murphy, K. S. Echtay, F. H. Blaikie et al., “Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from α-phenyl-N-tert-butylnitrone,” Journal of Biological Chemistry, vol. 278, no. 49, pp. 48534–48545, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. T. C. Esteves and M. D. Brand, “The reactions catalysed by the mitochondrial uncoupling proteins UCP2 and UCP3,” Biochimica et Biophysica Acta, vol. 1709, no. 1, pp. 35–44, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. C. Pecqueur, C. Alves-Guerra, D. Ricquier, and F. Bouillaud, “UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism?” IUBMB Life, vol. 61, no. 7, pp. 762–767, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. C. Pecqueur, T. Bui, C. Gelly et al., “Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization,” FASEB Journal, vol. 22, no. 1, pp. 9–18, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. C. Y. Zhang, G. Baffy, P. Perret et al., “Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes,” Cell, vol. 105, no. 6, pp. 745–755, 2001. View at Publisher · View at Google Scholar
  30. Z. B. Andrews and T. L. Horvath, “Uncoupling protein-2 regulates lifespan in mice,” American Journal of Physiology, vol. 296, no. 4, pp. E621–E627, 2009. View at Publisher · View at Google Scholar
  31. Z. Derdak, N. M. Mark, G. Beldi, S. C. Robson, J. R. Wands, and G. Baffy, “The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells,” Cancer Research, vol. 68, no. 8, pp. 2813–2819, 2008. View at Publisher · View at Google Scholar · View at PubMed
  32. D. Arsenijevic, H. Onuma, C. Pecqueur et al., “Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production,” Nature Genetics, vol. 26, no. 4, pp. 435–439, 2000. View at Publisher · View at Google Scholar · View at PubMed
  33. J. Pi and S. Collins, “Reactive oxygen species and uncoupling protein 2 in pancreatic β-cell function,” Diabetes, Obesity and Metabolism, vol. 12, supplement 2, pp. 141–148, 2010. View at Publisher · View at Google Scholar
  34. H. Esterbauer, H. Oberkofler, F. Krempler, A. D. Strosberg, and W. Patsch, “The uncoupling protein-3 gene is transcribed from tissue-specific promoters in humans but not in rodents,” Journal of Biological Chemistry, vol. 275, no. 46, pp. 36394–36399, 2000. View at Publisher · View at Google Scholar
  35. G. Solanes, A. Vidal-Puig, D. Grujic, J. S. Flier, and B. B. Lowell, “The human uncoupling protein-3 gene. Genomic structure, chromosomal localization, and genetic basis for short and long form transcripts,” Journal of Biological Chemistry, vol. 272, no. 41, pp. 25433–25436, 1997. View at Publisher · View at Google Scholar
  36. C. B. Chan, P. E. MacDonald, M. C. Saleh, D. C. Johns, E. Marbàn, and M. B. Wheeler, “Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets,” Diabetes, vol. 48, no. 7, pp. 1482–1486, 1999. View at Publisher · View at Google Scholar
  37. C. B. Chan, “Endogenous regulation of insulin secretion by UCP2,” Clinical Laboratory, vol. 48, no. 11-12, pp. 599–604, 2002. View at Google Scholar
  38. C. B. Chan, D. De Leo, J. W. Joseph et al., “Increased uncoupling protein-2 levels in β-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action,” Diabetes, vol. 50, no. 6, pp. 1302–1310, 2001. View at Google Scholar
  39. S. Krauss, C. Y. Zhang, L. Scorrano et al., “Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1831–1842, 2003. View at Publisher · View at Google Scholar
  40. J. W. Joseph, V. Koshkin, C. Y. Zhang et al., “Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet,” Diabetes, vol. 51, no. 11, pp. 3211–3219, 2002. View at Google Scholar
  41. J. W. Joseph, V. Koshkin, M. C. Saleh et al., “Free fatty acid-induced β-cell defects are dependent on uncoupling protein 2 expression,” Journal of Biological Chemistry, vol. 279, no. 49, pp. 51049–51056, 2004. View at Publisher · View at Google Scholar · View at PubMed
  42. C. T. De Souza, E. P. Araújo, L. F. Stoppiglia et al., “Inhibition of UCP2 expression reverses diet-induced diabetes mellitus by effects on both insulin secretion and action,” FASEB Journal, vol. 21, no. 4, pp. 1153–1163, 2007. View at Publisher · View at Google Scholar · View at PubMed
  43. J. Pi, Y. Bai, K. W. Daniel et al., “Persistent oxidative stress due to absence of uncoupling protein 2 associated with impaired pancreatic β-cell function,” Endocrinology, vol. 150, no. 7, pp. 3040–3048, 2009. View at Publisher · View at Google Scholar
  44. R. N. Kulkarni, “Uncoupling modifier genes from uncoupling protein 2 in pancreatic β-cells,” Endocrinology, vol. 150, no. 7, pp. 2994–2996, 2009. View at Publisher · View at Google Scholar
  45. Y. Li, K. Maedler, and L. Haataja, “UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells,” PLoS ONE, vol. 3, no. 1, Article ID e1397, 2008. View at Publisher · View at Google Scholar · View at PubMed
  46. A. J. Vidal-Puig, D. Grujic, C. Y. Zhang et al., “Energy metabolism in uncoupling protein 3 gene knockout mice,” Journal of Biological Chemistry, vol. 275, no. 21, pp. 16258–16266, 2000. View at Publisher · View at Google Scholar · View at PubMed
  47. D. W. Gong, S. Monemdjou, O. Gavrilova et al., “Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3,” Journal of Biological Chemistry, vol. 275, no. 21, pp. 16251–16257, 2000. View at Publisher · View at Google Scholar
  48. J. C. Clapham, J. R. S. Arch, H. Chapman et al., “Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean,” Nature, vol. 406, no. 6794, pp. 415–418, 2000. View at Publisher · View at Google Scholar · View at PubMed
  49. T. L. Horvath, S. Diano, S. Miyamoto et al., “Uncoupling proteins-2 and 3 influence obesity and inflammation in transgenic mice,” International Journal of Obesity, vol. 27, no. 4, pp. 433–442, 2003. View at Publisher · View at Google Scholar · View at PubMed
  50. W. G. Sheldon, T. J. Bucci, R. W. Hart, and A. Turturro, “Age-related neoplasia in a lifetime study of ad libitum-fed and food- restricted B6C3F1 mice,” Toxicologic Pathology, vol. 23, no. 4, pp. 458–476, 1995. View at Google Scholar
  51. M. D. Brand, J. A. Buckingham, T. C. Esteves et al., “Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production,” Biochemical Society Symposium, vol. 71, pp. 203–213, 2004. View at Google Scholar
  52. M. Horimoto, M. B. Resnick, T. A. Konkin, J. Routhier, J. R. Wands, and G. Baffy, “Expression of uncoupling protein-2 in human colon cancer,” Clinical Cancer Research, vol. 10, no. 18, part 1, pp. 6203–6207, 2004. View at Publisher · View at Google Scholar · View at PubMed
  53. M. A. Paulik, R. G. Buckholz, M. E. Lancaster et al., “Development of infrared imaging to measure thermogenesis in cell culture: thermogenic effects of uncoupling protein-2, troglitazone, and β-adrenoceptor agonists,” Pharmaceutical Research, vol. 15, no. 6, pp. 944–949, 1998. View at Publisher · View at Google Scholar
  54. D. F. S. Rolfe and G. C. Brown, “Cellular energy utilization and molecular origin of standard metabolic rate in mammals,” Physiological Reviews, vol. 77, no. 3, pp. 731–758, 1997. View at Google Scholar
  55. N. Houstis, E. D. Rosen, and E. S. Lander, “Reactive oxygen species have a causal role in multiple forms of insulin resistance,” Nature, vol. 440, no. 7086, pp. 944–948, 2006. View at Publisher · View at Google Scholar · View at PubMed
  56. E. Chevillotte, M. Giralt, B. Miroux, D. Ricquier, and F. Villarroya, “Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production,” Diabetes, vol. 56, no. 4, pp. 1042–1050, 2007. View at Publisher · View at Google Scholar · View at PubMed
  57. J. Blanc, M. C. Alves-Guerra, B. Esposito et al., “Protective role of uncoupling protein 2 in atherosclerosis,” Circulation, vol. 107, no. 3, pp. 388–390, 2003. View at Publisher · View at Google Scholar
  58. T. Nishikawa, D. Edelstein, X. L. Du et al., “Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage,” Nature, vol. 404, no. 6779, pp. 787–790, 2000. View at Publisher · View at Google Scholar · View at PubMed
  59. M. H. Cha, I. C. Kim, K. S. Kim, B. K. Kang, S. M. Choi, and Y. Yoon, “Association of UCP2 and UCP3 gene polymorphisms with serum high-density lipoprotein cholesterol among Korean women,” Metabolism, vol. 56, no. 6, pp. 806–813, 2007. View at Publisher · View at Google Scholar · View at PubMed
  60. L. T. Dalgaard, G. Andersen, L. H. Larsen et al., “Mutational analysis of the UCP2 core promoter and relationships of variants with obesity,” Obesity Research, vol. 11, no. 11, pp. 1420–1427, 2003. View at Google Scholar
  61. S. A. Urhammer, L. T. Dalgaard, T. I. A. Sørensen et al., “Mutational analysis of the coding region of the uncoupling protein 2 gene in obese NIDDM patients: impact of a common amino acid polymorphism on juvenile and maturity onset forms of obesity and insulin resistance,” Diabetologia, vol. 40, no. 10, pp. 1227–1230, 1997. View at Publisher · View at Google Scholar
  62. L. T. Dalgaard, T. I. A. Sørensen, T. Andersen, T. Hansen, and O. Pedersen, “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, vol. 42, no. 12, pp. 1413–1416, 1999. View at Publisher · View at Google Scholar
  63. L. T. Dalgaard, T. I. A. Sørensen, T. Drivsholm et al., “A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 3, pp. 1398–1402, 2001. View at Publisher · View at Google Scholar
  64. C. Pecqueur, A. M. Cassard-Doulcier, S. Raimbault et al., “Functional organization of the human uncoupling protein-2 gene, and juxtaposition to the uncoupling protein-3 gene,” Biochemical and Biophysical Research Communications, vol. 255, no. 1, pp. 40–46, 1999. View at Publisher · View at Google Scholar
  65. L. T. Dalgaard, T. Hansen, S. A. Urhammer, T. Drivsholm, K. Borch-Johnsen, and O. Pedersen, “The uncoupling protein 3-55 C→T variant is not associated with type II diabetes mellitus in Danish subjects,” Diabetologia, vol. 44, no. 8, pp. 1065–1067, 2001. View at Publisher · View at Google Scholar
  66. P. G. Cassell, P. J. Saker, S. J. Huxtable 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, vol. 43, no. 12, pp. 1558–1564, 2000. View at Publisher · View at Google Scholar
  67. T. Berentzen, L. T. Dalgaard, L. Petersen, O. Pedersen, and T. I. A. Sørensen, “Interactions between physical activity and variants of the genes encoding uncoupling proteins -2 and -3 in relation to body weight changes during a 10-y follow-up,” International Journal of Obesity, vol. 29, no. 1, pp. 93–99, 2005. View at Publisher · View at Google Scholar · View at PubMed
  68. A. M. Brown, J. W. Dolan, S. M. Willi, W. T. Garvey, and G. Argyropoulos, “Endogenous mutations in human uncoupling protein 3 alter its functional properties,” FEBS Letters, vol. 464, no. 3, pp. 189–193, 1999. View at Publisher · View at Google Scholar
  69. A. M. Brown, S. M. Willi, G. Argyropoulos, and W. T. Garvey, “A novel missense mutation, R70W, in the human uncoupling protein 3 gene in a family with type 2 diabetes,” Human Mutation, vol. 13, p. 506, 1999. View at Google Scholar
  70. F. Krempler, H. Esterbauer, R. Weitgasser 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, vol. 51, no. 11, pp. 3331–3335, 2002. View at Google Scholar
  71. M. Sasahara, M. Nishi, H. Kawashima et al., “Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients,” Diabetes, vol. 53, no. 2, pp. 482–485, 2004. View at Publisher · View at Google Scholar
  72. G. Sesti, M. Cardellini, M. A. Marini et al., “A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects,” Diabetes, vol. 52, no. 5, pp. 1280–1283, 2003. View at Publisher · View at Google Scholar
  73. H. Wang, W. S. Chu, T. Lu, S. J. Hasstedt, P. A. Kern, and S. C. Elbein, “Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion,” American Journal of Physiology, vol. 286, no. 1, pp. E1–E7, 2004. View at Google Scholar
  74. H. Esterbauer, C. Schneitler, H. Oberkofler et al., “A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans,” Nature Genetics, vol. 28, no. 2, pp. 178–183, 2001. View at Publisher · View at Google Scholar · View at PubMed
  75. H. S. Jun, I. K. Kim, H. J. Lee et al., “Effects of UCP2 and UCP3 variants on the manifestation of overweight in Korean children,” Obesity, vol. 17, no. 2, pp. 355–362, 2009. View at Publisher · View at Google Scholar
  76. M. C. Ochoa, J. L. Santos, C. Azcona et al., “Association between obesity and insulin resistance with UCP2-UCP3 gene variants in Spanish children and adolescents,” Molecular Genetics and Metabolism, vol. 92, no. 4, pp. 351–358, 2007. View at Publisher · View at Google Scholar · View at PubMed
  77. S. S. Dhamrait, J. W. Stephens, J. A. Cooper et al., “FT Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2,” European Heart Journal, vol. 25, no. 6, pp. 468–475, 2004. View at Publisher · View at Google Scholar · View at PubMed
  78. S. I. Kring, L. H. Larsen, C. Holst et al., “Genotype-phenotype associations in obesity dependent on definition of the obesity phenotype,” Obesity Facts, vol. 1, no. 3, pp. 138–145, 2008. View at Publisher · View at Google Scholar
  79. F. P. Mancini, L. Sabatino, V. Colantuoni et al., “Variants of uncoupling protein-2 gene and obesity: interaction with peroxisome proliferator-activated receptorγ2,” Clinical Endocrinology, vol. 59, no. 6, pp. 817–822, 2003. View at Publisher · View at Google Scholar · View at PubMed
  80. M. D'Adamo, L. Perego, M. Cardellini 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, vol. 53, no. 7, pp. 1905–1910, 2004. View at Publisher · View at Google Scholar
  81. Q. Ji, H. Ikegami, T. Fujisawa et al., “A common polymorphism of uncoupling protein 2 gene is associated with hypertension,” Journal of Hypertension, vol. 22, no. 1, pp. 97–102, 2004. View at Publisher · View at Google Scholar
  82. A. Bulotta, O. Ludovico, A. Coco et al., “The common -866G/A polymorphism in the promoter region of the UCP-2 gene is associated with reduced risk of type 2 diabetes in Caucasians from Italy,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 2, pp. 1176–1180, 2005. View at Publisher · View at Google Scholar · View at PubMed
  83. P. Kovacs, L. Ma, R. L. Hanson et al., “Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians,” Diabetologia, vol. 48, no. 11, pp. 2292–2295, 2005. View at Publisher · View at Google Scholar · View at PubMed
  84. D. R. Gable, J. W. Stephens, S. S. Dhamrait, E. Hawe, and S. E. Humphries, “European differences in the association between the UCP2 -866G > A common gene variant and markers of body mass and fasting plasma insulin,” Diabetes, Obesity and Metabolism, vol. 9, no. 1, pp. 130–131, 2007. View at Publisher · View at Google Scholar · View at PubMed
  85. A. F. Marvelle, L. A. Lange, L. Qin, L. S. Adair, and K. L. Mohlke, “Association of FTO with obesity-related traits in the cebu longitudinal health and nutrition survey (CLHNS) cohort,” Diabetes, vol. 57, no. 7, pp. 1987–1991, 2008. View at Publisher · View at Google Scholar · View at PubMed
  86. N. Schäuble, F. Geller, W. Siegfried et al., “No evidence for involvement of the promoter polymorphism -866 G/A of the UCP2 gene in childhood-onset obesity in humans,” Experimental and Clinical Endocrinology and Diabetes, vol. 111, no. 2, pp. 73–76, 2003. View at Publisher · View at Google Scholar · View at PubMed
  87. Y. H. Hsu, T. Niu, Y. Song, L. Tinker, L. H. Kuller, and S. Liu, “Genetic variants in the UCP2-UCP3 gene cluster and risk of diabetes in the women's health initiative observational study,” Diabetes, vol. 57, no. 4, pp. 1101–1107, 2008. View at Publisher · View at Google Scholar · View at PubMed
  88. T. Salopuro, L. Pulkkinen, J. Lindström et al., “Variation in the UCP2 and UCP3 genes associates with abdominal obesity and serum lipids: the Finnish diabetes prevention study,” BMC Medical Genetics, vol. 10, Article ID 1471, p. 94, 2009. View at Publisher · View at Google Scholar
  89. S. Le Fur, C. Le Stunff, C. Dos Santos, and P. Bougnères, “The common -866 G/A polymorphism in the promoter of uncoupling protein 2 is associated with increased carbohydrate and decreased lipid oxidation in juvenile obesity,” Diabetes, vol. 53, no. 1, pp. 235–239, 2004. View at Publisher · View at Google Scholar
  90. A. F. Reis, D. Dubois-Laforgue, C. Bellanné-Chantelot, J. Timsit, and G. Velho, “A polymorphism in the promoter of UCP2 gene modulates lipid levels in patients with type 2 diabetes,” Molecular Genetics and Metabolism, vol. 82, no. 4, pp. 339–344, 2004. View at Publisher · View at Google Scholar · View at PubMed
  91. N. Srivastava, J. Prakash, R. Lakhan, C. G. Agarwal, D. C. Pant, and B. Mittal, “A common polymorphism in the promoter of UCP2 is associated with obesity and hyperinsulenemia in northern Indians,” Molecular and Cellular Biochemistry, vol. 337, no. 1-2, pp. 293–298, 2010. View at Publisher · View at Google Scholar
  92. Y. Yoon, B. L. Park, M. H. Cha et al., “Effects of genetic polymorphisms of UCP2 and UCP3 on very low calorie diet-induced body fat reduction in Korean female subjects,” Biochemical and Biophysical Research Communications, vol. 359, no. 3, pp. 451–456, 2007. View at Publisher · View at Google Scholar · View at PubMed
  93. L. T. Dalgaard and O. Pedersen, “Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes,” Diabetologia, vol. 44, no. 8, pp. 946–965, 2001. View at Publisher · View at Google Scholar · View at PubMed
  94. J. J. Jia, X. Zhang, C. R. Ge, and M. Jois, “The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes: etiology and pathophysiology,” Obesity Reviews, vol. 10, no. 5, pp. 519–526, 2009. View at Publisher · View at Google Scholar
  95. P. G. Cassell, M. Neverova, S. Janmohamed et al., “An uncoupling protein 2 gene variant is associated with a raised body mass index but not Type II diabetes,” Diabetologia, vol. 42, no. 6, pp. 688–692, 1999. View at Publisher · View at Google Scholar
  96. B. Buemann, B. Schierning, S. Toubro et al., “The association between the val/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency,” International Journal of Obesity, vol. 25, no. 4, pp. 467–471, 2001. View at Publisher · View at Google Scholar
  97. K. Walder, R. A. Norman, R. L. Hanson et al., “Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians,” Human Molecular Genetics, vol. 7, no. 9, pp. 1431–1435, 1998. View at Publisher · View at Google Scholar
  98. M. M. González-Barroso, I. Giurgea, F. Bouillaud et al., “Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion,” PLoS ONE, vol. 3, no. 12, Article ID e3850, 2008. View at Publisher · View at Google Scholar
  99. D. R. Gable, J. W. Stephens, J. A. Cooper, G. J. Miller, and S. E. Humphries, “Variation in the UCP2-UCP3 gene cluster predicts the development of type 2 diabetes in healthy middle-aged men,” Diabetes, vol. 55, no. 5, pp. 1504–1511, 2006. View at Publisher · View at Google Scholar
  100. V. Lyssenko, P. Almgren, D. Anevski et al., “Genetic prediction of future type 2 diabetes,” PLoS Medicine, vol. 2, no. 12, Article ID e345, 2005. View at Publisher · View at Google Scholar · View at PubMed
  101. E. Rai, S. Sharma, A. Koul, A. K. Bhat, A. J. S. Bhanwer, and R. N. K. Bamezai, “Interaction between the UCP2-866G/A, mtDNA 10398G/A and PGC1α p.Thr394Thr and p.Gly482Ser polymorphisms in type 2 diabetes susceptibility in North Indian population,” Human Genetics, vol. 122, no. 5, pp. 535–540, 2007. View at Publisher · View at Google Scholar · View at PubMed
  102. N. Cheurfa, D. Dubois-Laforgue, D. A. F. Ferrarezi et al., “The common -866G > A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men,” Diabetes, vol. 57, no. 4, pp. 1063–1068, 2008. View at Publisher · View at Google Scholar · View at PubMed
  103. B. R. Palmer, C. L. Devereaux, S. S. Dhamrait et al., “The common G-866A polymorphism of the UCP2 gene and survival in diabetic patients following myocardial infarction,” Cardiovascular Diabetology, vol. 8, Article ID 31, 2009. View at Publisher · View at Google Scholar
  104. J. W. Stephens, S. S. Dhamrait, A. R. Mani et al., “Interaction between the uncoupling protein 2 -866G > A gene variant and cigarette smoking to increase oxidative stress in subjects with diabetes,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 18, no. 1, pp. 7–14, 2008. View at Publisher · View at Google Scholar · View at PubMed
  105. G. Rudofsky, A. Schroedter, A. Schlotterer et al., “Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes,” Diabetes Care, vol. 29, no. 1, pp. 89–94, 2006. View at Google Scholar
  106. I. Labayen, F. B. Ortega, M. Sjöström, T. K. Nilsson, L. A. Olsson, and J. R. Ruiz, “Association of common variants of UCP2 gene with low-grade inflammation in Swedish children and adolescents; The European Youth Heart Study,” Pediatric Research, vol. 66, no. 3, pp. 350–354, 2009. View at Publisher · View at Google Scholar
  107. E. Lapice, M. Pinelli, E. Pisu et al., “Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients C-reactive protein in type 2 diabetic patients,” Cardiovascular Diabetology, vol. 9, article 68, 2010. View at Publisher · View at Google Scholar
  108. G. Rudofsky, A. Schrödter, O. E. Voron'ko et al., “Promoter polymorphisms of UCP1, UCP2, and UCP3 are not associated with diabetic microvascular complications in type 2 diabetes,” Hormone and Metabolic Research, vol. 39, no. 4, pp. 306–309, 2007. View at Publisher · View at Google Scholar · View at PubMed
  109. B. F. Voight, L. J. Scott, V. Steinthorsdottir et al., “Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis,” Nature Genetics, vol. 42, no. 7, pp. 579–589, 2010. View at Publisher · View at Google Scholar
  110. E. K. Speliotes, C. J. Willer, S. I. Berndt et al., “Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index,” Nature Genetics, vol. 42, no. 11, pp. 937–948, 2010. View at Publisher · View at Google Scholar · View at PubMed