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. 1998 Oct 1;102(7):1345–1351. doi: 10.1172/JCI4115

Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes.

G Argyropoulos 1, A M Brown 1, S M Willi 1, J Zhu 1, Y He 1, M Reitman 1, S M Gevao 1, I Spruill 1, W T Garvey 1
PMCID: PMC508981  PMID: 9769326

Abstract

Human uncoupling protein 3 (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative ATP phosphorylation. With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. A missense polymorphism in exon 3 (V102I) was identified in an obese and diabetic proband. A mutation introducing a stop codon in exon 4 (R143X) and a terminal polymorphism in the splice donor junction of exon 6 were also identified in a compound heterozygote that was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6-splice donor heterozygotes, basal fat oxidation rates were reduced by 50%, and the respiratory quotient was markedly increased compared with wild-type individuals, implicating a role for UCP3 in metabolic fuel partitioning.

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Selected References

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  1. Argyropoulos G., Brown A. M., Peterson R., Likes C. E., Watson D. K., Garvey W. T. Structure and organization of the human uncoupling protein 2 gene and identification of a common biallelic variant in Caucasian and African-American subjects. Diabetes. 1998 Apr;47(4):685–687. doi: 10.2337/diabetes.47.4.685. [DOI] [PubMed] [Google Scholar]
  2. Bienengraeber M., Echtay K. S., Klingenberg M. H+ transport by uncoupling protein (UCP-1) is dependent on a histidine pair, absent in UCP-2 and UCP-3. Biochemistry. 1998 Jan 6;37(1):3–8. doi: 10.1021/bi972463w. [DOI] [PubMed] [Google Scholar]
  3. Boss O., Samec S., Paoloni-Giacobino A., Rossier C., Dulloo A., Seydoux J., Muzzin P., Giacobino J. P. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 1997 May 12;408(1):39–42. doi: 10.1016/s0014-5793(97)00384-0. [DOI] [PubMed] [Google Scholar]
  4. Bouchard C., Pérusse L., Chagnon Y. C., 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 Oct;6(11):1887–1889. doi: 10.1093/hmg/6.11.1887. [DOI] [PubMed] [Google Scholar]
  5. Cassard A. M., Bouillaud F., Mattei M. G., Hentz E., Raimbault S., Thomas M., Ricquier D. Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4. J Cell Biochem. 1990 Jul;43(3):255–264. doi: 10.1002/jcb.240430306. [DOI] [PubMed] [Google Scholar]
  6. Chakraborty R., Kamboh M. I., Nwankwo M., Ferrell R. E. Caucasian genes in American blacks: new data. Am J Hum Genet. 1992 Jan;50(1):145–155. [PMC free article] [PubMed] [Google Scholar]
  7. Eberhardt M. S., Lackland D. T., Wheeler F. C., German R. R., Teutsch S. M. Is race related to glycemic control? An assessment of glycosylated hemoglobin in two South Carolina communities. J Clin Epidemiol. 1994 Oct;47(10):1181–1189. doi: 10.1016/0895-4356(94)90105-8. [DOI] [PubMed] [Google Scholar]
  8. Fleury C., Neverova M., Collins S., Raimbault S., Champigny O., Levi-Meyrueis C., Bouillaud F., Seldin M. F., Surwit R. S., Ricquier D. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997 Mar;15(3):269–272. doi: 10.1038/ng0397-269. [DOI] [PubMed] [Google Scholar]
  9. Friedman J. M. The alphabet of weight control. Nature. 1997 Jan 9;385(6612):119–120. doi: 10.1038/385119a0. [DOI] [PubMed] [Google Scholar]
  10. Gong D. W., He Y., Karas M., Reitman M. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem. 1997 Sep 26;272(39):24129–24132. doi: 10.1074/jbc.272.39.24129. [DOI] [PubMed] [Google Scholar]
  11. Jackson R. S., Creemers J. W., Ohagi S., Raffin-Sanson M. L., Sanders L., Montague C. T., Hutton J. C., O'Rahilly S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997 Jul;16(3):303–306. doi: 10.1038/ng0797-303. [DOI] [PubMed] [Google Scholar]
  12. Jakicic J. M., Wing R. R. Differences in resting energy expenditure in African-American vs Caucasian overweight females. Int J Obes Relat Metab Disord. 1998 Mar;22(3):236–242. doi: 10.1038/sj.ijo.0800575. [DOI] [PubMed] [Google Scholar]
  13. Jezek P., Orosz D. E., Modriansky M., Garlid K. D. Transport of anions and protons by the mitochondrial uncoupling protein and its regulation by nucleotides and fatty acids. A new look at old hypotheses. J Biol Chem. 1994 Oct 21;269(42):26184–26190. [PubMed] [Google Scholar]
  14. Kennedy A., Gettys T. W., Watson P., Wallace P., Ganaway E., Pan Q., Garvey W. T. The metabolic significance of leptin in humans: gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. J Clin Endocrinol Metab. 1997 Apr;82(4):1293–1300. doi: 10.1210/jcem.82.4.3859. [DOI] [PubMed] [Google Scholar]
  15. Larkin S., Mull E., Miao W., Pittner R., Albrandt K., Moore C., Young A., Denaro M., Beaumont K. Regulation of the third member of the uncoupling protein family, UCP3, by cold and thyroid hormone. Biochem Biophys Res Commun. 1997 Nov 7;240(1):222–227. doi: 10.1006/bbrc.1997.7636. [DOI] [PubMed] [Google Scholar]
  16. Matsuda J., Hosoda K., Itoh H., Son C., Doi K., Tanaka T., Fukunaga Y., Inoue G., Nishimura H., Yoshimasa Y. Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their gene expression in rats fed high-fat diet. FEBS Lett. 1997 Nov 24;418(1-2):200–204. doi: 10.1016/s0014-5793(97)01381-1. [DOI] [PubMed] [Google Scholar]
  17. Millet L., Vidal H., Andreelli F., Larrouy D., Riou J. P., Ricquier D., Laville M., Langin D. Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. J Clin Invest. 1997 Dec 1;100(11):2665–2670. doi: 10.1172/JCI119811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Modrianský M., Murdza-Inglis D. L., Patel H. V., Freeman K. B., Garlid K. D. Identification by site-directed mutagenesis of three arginines in uncoupling protein that are essential for nucleotide binding and inhibition. J Biol Chem. 1997 Oct 3;272(40):24759–24762. doi: 10.1074/jbc.272.40.24759. [DOI] [PubMed] [Google Scholar]
  19. Montague C. T., Farooqi I. S., Whitehead J. P., Soos M. A., Rau H., Wareham N. J., Sewter C. P., Digby J. E., Mohammed S. N., Hurst J. A. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997 Jun 26;387(6636):903–908. doi: 10.1038/43185. [DOI] [PubMed] [Google Scholar]
  20. Murdza-Inglis D. L., Modriansky M., Patel H. V., Woldegiorgis G., Freeman K. B., Garlid K. D. A single mutation in uncoupling protein of rat brown adipose tissue mitochondria abolishes GDP sensitivity of H+ transport. J Biol Chem. 1994 Mar 11;269(10):7435–7438. [PubMed] [Google Scholar]
  21. Peters A. L., Davidson M. B., Schriger D. L., Hasselblad V. A clinical approach for the diagnosis of diabetes mellitus: an analysis using glycosylated hemoglobin levels. Meta-analysis Research Group on the Diagnosis of Diabetes Using Glycated Hemoglobin Levels. JAMA. 1996 Oct 16;276(15):1246–1252. [PubMed] [Google Scholar]
  22. Pollitzer W. S., Boyle E., Jr, Cornoni J., Namboodiri K. K. Physical anthropology of the Negroes of Charleston, S. C. Hum Biol. 1970 May;42(2):265–279. [PubMed] [Google Scholar]
  23. Ravussin E. Metabolic differences and the development of obesity. Metabolism. 1995 Sep;44(9 Suppl 3):12–14. doi: 10.1016/0026-0495(95)90312-7. [DOI] [PubMed] [Google Scholar]
  24. Samec S., Seydoux J., Dulloo A. G. Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate? FASEB J. 1998 Jun;12(9):715–724. doi: 10.1096/fasebj.12.9.715. [DOI] [PubMed] [Google Scholar]
  25. Silva J. E., Rabelo R. Regulation of the uncoupling protein gene expression. Eur J Endocrinol. 1997 Mar;136(3):251–264. doi: 10.1530/eje.0.1360251. [DOI] [PubMed] [Google Scholar]
  26. Solanes G., Vidal-Puig A., Grujic D., Flier J. S., Lowell B. B. The human uncoupling protein-3 gene. Genomic structure, chromosomal localization, and genetic basis for short and long form transcripts. J Biol Chem. 1997 Oct 10;272(41):25433–25436. doi: 10.1074/jbc.272.41.25433. [DOI] [PubMed] [Google Scholar]
  27. Solovyev V. V., Salamov A. A. Predicting alpha-helix and beta-strand segments of globular proteins. Comput Appl Biosci. 1994 Dec;10(6):661–669. doi: 10.1093/bioinformatics/10.6.661. [DOI] [PubMed] [Google Scholar]
  28. Strobel A., Issad T., Camoin L., Ozata M., Strosberg A. D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998 Mar;18(3):213–215. doi: 10.1038/ng0398-213. [DOI] [PubMed] [Google Scholar]
  29. Surwit R. S., Wang S., Petro A. E., Sanchis D., Raimbault S., Ricquier D., Collins S. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4061–4065. doi: 10.1073/pnas.95.7.4061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Urhammer S. A., Dalgaard L. T., Sørensen T. I., Tybjaerg-Hansen A., Echwald S. M., Andersen T., Clausen J. O., Pedersen O. Organisation of the coding exons and mutational screening of the uncoupling protein 3 gene in subjects with juvenile-onset obesity. Diabetologia. 1998 Feb;41(2):241–244. doi: 10.1007/s001250050897. [DOI] [PubMed] [Google Scholar]
  31. Vidal-Puig A., Solanes G., Grujic D., Flier J. S., Lowell B. B. UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun. 1997 Jun 9;235(1):79–82. doi: 10.1006/bbrc.1997.6740. [DOI] [PubMed] [Google Scholar]
  32. Weigle D. S., Selfridge L. E., Schwartz M. W., Seeley R. J., Cummings D. E., Havel P. J., Kuijper J. L., BeltrandelRio H. Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential explanation for the effect of fasting. Diabetes. 1998 Feb;47(2):298–302. doi: 10.2337/diab.47.2.298. [DOI] [PubMed] [Google Scholar]
  33. Winkler E., Wachter E., Klingenberg M. Identification of the pH sensor for nucleotide binding in the uncoupling protein from brown adipose tissue. Biochemistry. 1997 Jan 7;36(1):148–155. doi: 10.1021/bi962178x. [DOI] [PubMed] [Google Scholar]
  34. Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J. M. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994 Dec 1;372(6505):425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]

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