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Gene Review

UCP1  -  uncoupling protein 1 (mitochondrial,...

Homo sapiens

Synonyms: Mitochondrial brown fat uncoupling protein 1, SLC25A7, Solute carrier family 25 member 7, Thermogenin, UCP, ...
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Disease relevance of UCP1

  • The three uncoupling protein homologue genes UCP1, UCP2, and UCP3 have been investigated for polymorphisms and mutations and their impact on Type II diabetes mellitus, obesity, and body weight gain or BMI [1].
  • The main conclusion is that variation in the UCP1, UCP2 or UCP3 genes is not associated with major alterations of body weight gain [1].
  • RESULTS: No effect of the A-3826G polymorphism in the UCP1 gene on diabetes complications was found [2].
  • Also [3H]GTP ([3H]ATP) binding to isolated Escherichia coli (Kd, approximately 5 microm) or yeast-expressed UCP2 (Kd, approximately 1.5 microm) or UCP3 exhibited high affinity, similar to UCP1 [3].
  • Genetic variants of the coding region as well as a previously described a-->g nucleotide polymorphism of the 5'-flanking region of the UCP1 gene were examined for associations with accelerated weight gain or reduced sensitivity to insulin in a cohort of 380 young healthy Caucasians [4].

Psychiatry related information on UCP1

  • No evidence for interaction between the UCP-variants and physical activity was found in relation to the additional obesity measures [5].
  • Thus, reduction in hamster BAT thermogenic capacity during food deprivation may occur by loss of cells and (or)reduction in the tissue protein and thermogenin contents [6].

High impact information on UCP1

  • The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings [7].
  • Reduced mass, GDP binding to brown fat mitochondria, and uncoupling protein (UCP) levels are cited as evidence for attenuated brown adipose tissue cold-induced nonshivering thermogenic capacity during aging [8].
  • We now report the discovery of a gene that codes for a novel uncoupling protein, designated UCP2, which has 59% amino-acid identity to UCP1, and describe properties consistent with a role in diabetes and obesity [9].
  • In comparison with UCP1, UCP2 has a greater effect on mitochondrial membrane potential when expressed in yeast [9].
  • Compared to UCP1, the gene is widely expressed in adult human tissues, including tissues rich in macrophages, and it is upregulated in white fat in response to fat feeding [9].

Chemical compound and disease context of UCP1


Biological context of UCP1

  • UCP1 induces heat production by uncoupling respiration from ATP synthesis [14].
  • The brown adipose tissue (BAT) UCP1 has a marked and strongly regulated uncoupling activity, essential to the maintenance of body temperature in small mammals [15].
  • The novel UCP3 was 57% and 73% identical to human UCP1 and UCP2, respectively, highly skeletal muscle-specific and its expression was unaffected by cold acclimation [16].
  • UCP1 is considered to mediate purine nucleotide-sensitive uniport of monovalent unipolar anions, including anionic fatty acids [17].
  • The role of specific residues in UCP1 is analyzed by directed mutagenesis in a yeast expression system [18].

Anatomical context of UCP1

  • The GDP-sensitive proton conductance induced by hydroxynonenal correlated with tissue expression of UCPs, appeared in yeast mitochondria expressing UCP1 and was absent in skeletal muscle mitochondria from UCP3 knockout mice [19].
  • In contrast to UCP1, which is only present in brown adipose tissue, UCP2 has a wide tissue distribution, whereas UCP3 is expressed predominantly in skeletal muscle [20].
  • From the three different UCPs identified so far by gene cloning UCP1 is expressed exclusively in brown adipocytes while UCP2 is widely expressed [21].
  • Until very recently, the uncoupling protein-1 (UCP1), present only in brown adipose tissue (BAT), was considered to be the only mitochondrial carrier protein that stimulated heat production by dissipating the proton gradient generated during respiration across the inner mitochondrial membrane and therefore uncoupling respiration from ATP synthesis [22].
  • The expression levels of UCP-1 and UCP-2 in BAT and in skeletal and cardiac muscle respectively were not affected by variations in tissue LPL activities [23].

Associations of UCP1 with chemical compounds

  • We also examined the effect of coenzyme Q on fatty acid-catalyzed proton flux in liposomes containing recombinant UCP1, -2, and -3 [24].
  • Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10 [24].
  • At high levels of glucose, expression of UCP1, UCP2 and MnSOD increased to accommodate ROS production compensatively [25].
  • Accordingly, the addition of retinoic acid uncouples the respiration of the UCP1-expressing clone, but not that of the UCP3-expressing ones [26].
  • A model is proposed using the known passive transport of pyruvate by UCP1 [26].

Enzymatic interactions of UCP1

  • UCP1 catalyses a regulated inducible proton conductance in brown adipose tissue and the possibility remains open that UCP2 and UCP3 have a similar role in other tissues, although this has yet to be demonstrated [27].

Regulatory relationships of UCP1

  • In these cells, UCP1 acts as a proton carrier activated by free fatty acids and creates a shunt between complexes of the respiratory chain and ATP synthase [28].
  • Binding studies using the new labelled beta 3 adrenergic ligand [3H]SB 206606 showed a density of beta 3-AR in brown adipocyte plasma membranes comparable to that measured in vivo. beta 3-AR mRNA expression was very high in mature brown adipocytes and was started to be expressed during differentiation before UCP mRNA [29].

Other interactions of UCP1


Analytical, diagnostic and therapeutic context of UCP1

  • RESEARCH DESIGN AND METHODS: We analyzed 227 patients with type 1 diabetes using PCR and subsequent cleavage by restriction endonucleases for the promoter variants A-3826G in the UCP1 gene, G-866A in the UCP2 gene, and C-55T in the UCP3 gene [2].
  • UCP1, 2 and 3 mRNA expression in lean mice did not show any significant change after treatment with GH [34].
  • Zidovudine-based HAART recipients (n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA [35].
  • Single-strand conformation polymorphism and heteroduplex analysis of the coding region of the UCP1 gene was performed in 56 subjects randomly selected at the draft board examination from a cohort of 156 males with juvenile-onset obesity [4].
  • Although UCP1 is known to influence mitochondrial proton leak in vitro and core body temperature in mice, genetic studies in humans have produced only weak evidence for association of naturally occurring variants with body-mass index (BMI); the best-reported P value is 0.01 [36].


  1. Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes. Dalgaard, L.T., Pedersen, O. Diabetologia (2001) [Pubmed]
  2. Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes. Rudofsky, G., Schroedter, A., Schlotterer, A., Voron'ko, O.E., Schlimme, M., Tafel, J., Isermann, B.H., Humpert, P.M., Morcos, M., Bierhaus, A., Nawroth, P.P., Hamann, A. Diabetes Care (2006) [Pubmed]
  3. Activating omega-6 polyunsaturated fatty acids and inhibitory purine nucleotides are high affinity ligands for novel mitochondrial uncoupling proteins UCP2 and UCP3. Zackova, M., Skobisová, E., Urbánková, E., Jezek, P. J. Biol. Chem. (2003) [Pubmed]
  4. Studies of genetic variability of the uncoupling protein 1 gene in Caucasian subjects with juvenile-onset obesity. Urhammer, S.A., Fridberg, M., Sørensen, T.I., Echwald, S.M., Andersen, T., Tybjaerg-Hansen, A., Clausen, J.O., Pedersen, O. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  5. 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. Berentzen, T., Dalgaard, L.T., Petersen, L., Pedersen, O., Sørensen, T.I. International journal of obesity (2005) (2005) [Pubmed]
  6. Effects of fasting and food restriction on brown adipose tissue composition in normal and dystrophic hamsters. Desautels, M., Dulos, R.A., Yuen, H.M. Can. J. Physiol. Pharmacol. (1986) [Pubmed]
  7. Brown adipose tissue: function and physiological significance. Cannon, B., Nedergaard, J. Physiol. Rev. (2004) [Pubmed]
  8. Cold-induced thermoregulation and biological aging. Florez-Duquet, M., McDonald, R.B. Physiol. Rev. (1998) [Pubmed]
  9. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Fleury, C., Neverova, M., Collins, S., Raimbault, S., Champigny, O., Levi-Meyrueis, C., Bouillaud, F., Seldin, M.F., Surwit, R.S., Ricquier, D., Warden, C.H. Nat. Genet. (1997) [Pubmed]
  10. Synergistic effect of polymorphisms of uncoupling protein 1 and beta3-adrenergic receptor genes on autonomic nervous system activity. Shihara, N., Yasuda, K., Moritani, T., Ue, H., Uno, M., Adachi, T., Nunoi, K., Seino, Y., Yamada, Y., Tsuda, K. Int. J. Obes. Relat. Metab. Disord. (2001) [Pubmed]
  11. Decreased uncoupling protein expression and intramyocytic triglyceride depletion in formerly obese subjects. Mingrone, G., Rosa, G., Greco, A.V., Manco, M., Vega, N., Hesselink, M.K., Castagneto, M., Schrauwen, P., Vidal, H. Obes. Res. (2003) [Pubmed]
  12. The effects of norephedrine and bethanechol on the human urethral closure pressure profile. Ek, A., Andersson, K.E., Ulmsten, U. Scandinavian journal of urology and nephrology. (1978) [Pubmed]
  13. Recent developments in chest pain of undetermined origin. Achem, S.R., DeVault, K.R. Current gastroenterology reports. (2000) [Pubmed]
  14. Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. Millet, L., Vidal, H., Andreelli, F., Larrouy, D., Riou, J.P., Ricquier, D., Laville, M., Langin, D. J. Clin. Invest. (1997) [Pubmed]
  15. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Ricquier, D., Bouillaud, F. Biochem. J. (2000) [Pubmed]
  16. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. Boss, O., Samec, S., Paoloni-Giacobino, A., Rossier, C., Dulloo, A., Seydoux, J., Muzzin, P., Giacobino, J.P. FEBS Lett. (1997) [Pubmed]
  17. Fatty acid interaction with mitochondrial uncoupling proteins. Jezek, P. J. Bioenerg. Biomembr. (1999) [Pubmed]
  18. Uncoupling protein--a useful energy dissipator. Klingenberg, M. J. Bioenerg. Biomembr. (1999) [Pubmed]
  19. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. Echtay, K.S., Esteves, T.C., Pakay, J.L., Jekabsons, M.B., Lambert, A.J., Portero-Otín, M., Pamplona, R., Vidal-Puig, A.J., Wang, S., Roebuck, S.J., Brand, M.D. EMBO J. (2003) [Pubmed]
  20. Human uncoupling proteins and obesity. Schrauwen, P., Walder, K., Ravussin, E. Obes. Res. (1999) [Pubmed]
  21. Genomic organization and mutational analysis of the human UCP2 gene, a prime candidate gene for human obesity. Lentes, K.U., Tu, N., Chen, H., Winnikes, U., Reinert, I., Marmann, G., Pirke, K.M. J. Recept. Signal Transduct. Res. (1999) [Pubmed]
  22. The role of uncoupling proteins in pathophysiological states. Argilés, J.M., Busquets, S., López-Soriano, F.J. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  23. Tissue-specific activity of lipoprotein lipase in skeletal muscle regulates the expression of uncoupling protein 3 in transgenic mouse models. Kratky, D., Strauss, J.G., Zechner, R. Biochem. J. (2001) [Pubmed]
  24. Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10. Jaburek, M., Garlid, K.D. J. Biol. Chem. (2003) [Pubmed]
  25. Expression modification of uncoupling proteins and MnSOD in retinal endothelial cells and pericytes induced by high glucose: The role of reactive oxygen species in diabetic retinopathy. Cui, Y., Xu, X., Bi, H., Zhu, Q., Wu, J., Xia, X., Qiushi Ren, n.u.l.l., Ho, P.C. Exp. Eye Res. (2006) [Pubmed]
  26. Expression of UCP3 in CHO cells does not cause uncoupling, but controls mitochondrial activity in the presence of glucose. Mozo, J., Ferry, G., Studeny, A., Pecqueur, C., Rodriguez, M., Boutin, J.A., Bouillaud, F. Biochem. J. (2006) [Pubmed]
  27. The significance and mechanism of mitochondrial proton conductance. Brand, M.D., Brindle, K.M., Buckingham, J.A., Harper, J.A., Rolfe, D.F., Stuart, J.A. Int. J. Obes. Relat. Metab. Disord. (1999) [Pubmed]
  28. The biology of mitochondrial uncoupling proteins. Rousset, S., Alves-Guerra, M.C., Mozo, J., Miroux, B., Cassard-Doulcier, A.M., Bouillaud, F., Ricquier, D. Diabetes (2004) [Pubmed]
  29. Control of beta 3-adrenergic receptor gene expression in brown adipocytes in culture. Klaus, S., Muzzin, P., Revelli, J.P., Cawthorne, M.A., Giacobino, J.P., Ricquier, D. Mol. Cell. Endocrinol. (1995) [Pubmed]
  30. The mitochondrial uncoupling-protein homologues. Krauss, S., Zhang, C.Y., Lowell, B.B. Nat. Rev. Mol. Cell Biol. (2005) [Pubmed]
  31. Uncoupling proteins 2 and 3 are highly active H(+) transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone). Echtay, K.S., Winkler, E., Frischmuth, K., Klingenberg, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  32. Specific sequence of motifs of mitochondrial uncoupling proteins. Jezek, P., Urbánková, E. IUBMB Life (2000) [Pubmed]
  33. Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Harper, J.A., Dickinson, K., Brand, M.D. Obesity reviews : an official journal of the International Association for the Study of Obesity. (2001) [Pubmed]
  34. Effects of growth hormone (GH) on mRNA levels of uncoupling proteins 1, 2, and 3 in brown and white adipose tissues and skeletal muscle in obese mice. Hioki, C., Yoshida, T., Kogure, A., Takakura, Y., Umekawa, T., Yoshioka, K., Shimatsu, A., Yoshikawa, T. Horm. Metab. Res. (2004) [Pubmed]
  35. Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Pace, C.S., Martin, A.M., Hammond, E.L., Mamotte, C.D., Nolan, D.A., Mallal, S.A. Antivir. Ther. (Lond.) (2003) [Pubmed]
  36. Physiological effects of variants in human uncoupling proteins: UCP2 influences body-mass index. Schonfeld-Warden, N.A., Warden, C.H. Biochem. Soc. Trans. (2001) [Pubmed]
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