The term ‘uncoupling protein’ was originally used for the mitochondrial membrane protein UCP1, which is uniquely present in mitochondria of brown adipocytes, thermogenic cells that regulate body temperature in small rodents, hibernators and mammalian newborns. 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 resulting in a futile proton cycling and dissipation of oxidation energy as heat. Recent identification of new homologues to UCP1 expressed in brown and white adipose tissue, muscle, brain and other tissues together with the hypothesis that these novel uncoupling proteins (UCPs) may regulate thermogenesis and/or fatty acid metabolism and furthermore may protect against free radical oxygen species production have generated considerable optimism for rapid advances in the identification of new targets for pharmacological management of complex pathological syndromes such as obesity, type 2 diabetes or chronic inflammatory diseases. However, since the physiological and biochemical roles of the novel UCPs are not yet clear, the main challenge today consists first of all in providing mechanistic explanation for their functions in cellular physiology. This lively awaited information may be the basis for potential pharmacological targeting of the UCPs in future.

Keywords:
Uncoupling proteins, Energy metabolism, Thermogenesis, Body weight control, Mitochondria
1.
Brustovetsky NN, Amerkanov ZG, Yegorova ME, Mokhova EN, Skulachev VP: Carboxyatractylate-sensitive uncoupling in liver mitochondria from ground squirrels during hibernation and arousal. FEBS Lett 1990;272:190–192.
2.
Brustovetsky NN, Dedukhova VI, Egorova MV, Mokhova EN, Skulachev VP: Inhibitors of the ATP/ADP antiporter suppress stimulation of mitochondrial respiration and H+ permeability by palmitate and anionic detergents. FEBS Lett 1990;272:187–189.
3.
Brand MD, Pakay JL, Ocloo A, Kokoszka J, Wallace DC, Brookes PS, Cornwall EJ: The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem J 2005;392:353–362.
4.
Krauss S, Zhang CY, Lowell BB: The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 2005;6:248–261.
5.
Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F: Thermoregulation: what role for UCPs in mammals and birds? Biosci Rep 2005;25:227–249.
6.
Jezek P, Garlid KD: Mammalian mitochondrial uncoupling proteins. Int J Biochem Cell Biol 1998;30:1163–1168.
7.
Schrauwen P, Hesselink MK: The role of uncoupling protein 3 in fatty acid metabolism: protection against lipotoxicity? Proc Nutr Soc 2004;63:287–292.
8.
Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra MC, Goubern M, Surwit R, Bouillaud F, Richard D, Collins S, Ricquier D: Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000;26:435–439.
9.
Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, Pakay JL, Parker N: Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 2004;37:755–767.
10.
Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, Portero-Otin M, Pamplona R, Vidal-Puig AJ, Wang S, Roebuck SJ, Brand MD: A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J 2003;22:4103–4110.
11.
Chan CB, Saleh MC, Koshkin V, Wheeler MB: Uncoupling protein 2 and islet function. Diabetes 2004;53(suppl 1):S136–S142.
12.
Son C, Hosoda K, Ishihara K, Bevilacqua L, Masuzaki H, Fushiki T, Harper ME, Nakao K: Reduction of diet-induced obesity in transgenic mice overexpressing uncoupling protein 3 in skeletal muscle. Diabetologia 2004;47:47–54.
13.
Blanc J, Alves-Guerra MC, Esposito B, Rousset S, Gourdy P, Ricquier D, Tedgui A, Miroux B, Mallat Z: Protective role of uncoupling protein 2 in atherosclerosis. Circulation 2003;107:388–390.
14.
Brand MD, Buckingham JA, Esteves TC, Green K, Lambert AJ, Miwa S, Murphy MP, Pakay JL, Talbot DA, Echtay KS: Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production. Biochem Soc Symp 2004;71:203–213.
15.
Harper ME, Antoniou A, Villalobos-Menuey E, Russo A, Trauger R, Vendemelio M, George A, Bartholomew R, Carlo D, Shaikh A, Kupperman J, Newell EW, Bespalov IA, Wallace SS, Liu Y, Rogers JR, Gibbs GL, Leahy JL, Camley RE, Melamede R, Newell MK: Characterization of a novel metabolic strategy used by drug-resistant tumor cells. FASEB J 2002;16:1550–1557.
16.
Mills EM, Xu D, Fergusson MM, Combs CA, Xu Y, Finkel T: Regulation of cellular oncosis by uncoupling protein 2. J Biol Chem 2002;277:27385–27392.
17.
Brown GC: Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem J 1992;284:1–13.
18.
Kalckar HM: 50 years of biological research – from oxidative phosphorylation to energy requiring transport regulation. Annu Rev Biochem 1991;60:1–37.
19.
Palmieri F: The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflügers Arch 2004;447:689–709.
20.
Skulachev VP: Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta 1998;1363:100–124.
21.
Porter RK: Mitochondrial proton leak: a role for uncoupling proteins 2 and 3? Biochim Biophys Acta 2001;1504:120–127.
22.
Ricquier D, Bouillaud F: The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J 2000;345:161–179.
23.
Klingenberg M, Winkler E, Echtay K: Uncoupling protein, H+ transport and regulation. Biochem Soc Trans 2001;29:806–811.
24.
Sanchis D, Fleury C, Chomiki N, Goubern M, Huang Q, Neverova M, Gregoire F, Easlick J, Raimbault S, Levi-Meyrueis C, Miroux B, Collins S, Seldin M, Richard D, Warden C, Bouillaud F, Ricquier D: BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. J Biol Chem 1998;273:34611–34615.
25.
Haguenauer A, Raimbault S, Masscheleyn S, Gonzalez-Barroso Mdel M, Criscuolo F, Plamondon J, Miroux B, Ricquier D, Richard D, Bouillaud F, Pecqueur C: A new renal mitochondrial carrier, KMCP1, is up-regulated during tubular cell regeneration and induction of antioxidant enzymes. J Biol Chem 2005;280:22036–22043.
26.
Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH: Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997;15:269–272.
27.
Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP: Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 1997;408:39–42.
28.
Mao W, Yu XX, Zhong A, Li W, Brush J, Sherwood SW, Adams SH, Pan G: UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett 1999;443:326–330.
29.
Runswick MJ, Powell SJ, Nyren P, Walker JE: Sequence of the bovine mitochondrial phosphate carrier protein: structural relationship to ADP/ATP translocase and the brown fat mitochondria uncoupling protein. EMBO J 1987;6:1367–1373.
30.
Jezek P, Garlid KD: Mammalian mitochondrial uncoupling proteins. Int J Biochem Cell Biol 1998;30:1163–1168.
31.
Jezek P, Engstova H, Zackova M, Vercesi AE, Costa AD, Arruda P, Garlid KD: Fatty acid cycling mechanism and mitochondrial uncoupling proteins. Biochim Biophys Acta 1998;1365:319–327.
32.
Klingenspor M: Cold-induced recruitment of brown adipose tissue thermogenesis. Exp Physiol 2003;88:141–148.
33.
Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, Kozak LP: Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997;387:90–94.
34.
Harper ME, Gerrits MF: Mitochondrial uncoupling proteins as potential targets for pharmacological agents. Curr Opin Pharmacol 2004;4:603–607.
35.
Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM, Bouillaud F, Ricquier D: The biology of mitochondrial uncoupling proteins. Diabetes 2004;53(suppl 1):S130–S135.
36.
Bezaire V, Spriet LL, Campbell S, Sabet N, Gerrits M, Bonen A, Harper ME: Constitutive UCP3 overexpression at physiological levels increases mouse skeletal muscle capacity for fatty acid transport and oxidation. FASEB J 2005;19:977–979.
37.
Hong Y, Fink BD, Dillon JS, Sivitz WI: Effects of adenoviral overexpression of uncoupling protein-2 and -3 on mitochondrial respiration in insulinoma cells. Endocrinology 2001;142:249–256.
38.
Horvath TL, Warden CH, Hajos M, Lombardi A, Goglia F, Diano S: Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 1999;19:10417–10427.
39.
Andrews ZB, Diano S, Horvath TL: Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 2005;6:829–840.
40.
Nohl H, Kozlov AV, Gille L, Staniek K: Cell respiration and formation of reactive oxygen species: facts and artefacts. Biochem Soc Trans 2003;31:1308–1311.
41.
Negre-Salvayre A, Hirtz C, Carrera G, Cazenave R, Troly M, Salvayre R, Penicaud L, Casteilla L: A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J 1997;11:809–815.
42.
Bai Y, Onuma H, Bai X, Medvedev AV, Misukonis M, Weinberg JB, Cao W, Robidoux J, Floering LM, Daniel KW, Collins S: Persistent nuclear factor-kappa B activation in Ucp2–/– mice leads to enhanced nitric oxide and inflammatory cytokine production. J Biol Chem 2005;280:19062–19069.
43.
Alves-Guerra MC, Rousset S, Pecqueur C, Mallat Z, Blanc J, Tedgui A, Bouillaud F, Cassard-Doulcier AM, Ricquier D, Miroux B: Bone marrow transplantation reveals the in vivo expression of the mitochondrial uncoupling protein 2 in immune and nonimmune cells during inflammation. J Biol Chem 2003;278:42307–42312.
44.
Rousset S, Alves-Guerra MC, Ouadghiri-Bencherif S, Kozak LP, Miroux B, Richard D, Bouillaud F, Ricquier D, Cassard-Doulcier AM: Uncoupling protein 2, but not uncoupling protein 1, is expressed in the female mouse reproductive tract. J Biol Chem 2003;278:45843–45847.
45.
Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M: Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001;108:1341–1348.
46.
Park JY, Park KG, Kim HJ, Kang HG, Ahn JD, Kim HS, Kim YM, Son SM, Kim IJ, Kim YK, Kim CD, Lee KU, Lee IK: The effects of the overexpression of recombinant uncoupling protein 2 on proliferation, migration and plasminogen activator inhibitor 1 expression in human vascular smooth muscle cells. Diabetologia 2005;48:1022–1028.
47.
Bernal-Mizrachi C, Weng S, Li B, Nolte LA, Feng C, Coleman T, Holloszy JO, Semenkovich CF: Respiratory uncoupling lowers blood pressure through a leptin-dependent mechanism in genetically obese mice. Arterioscler Thromb Vasc Biol 2002;22:961–968.
48.
Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W: 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.
49.
Li B, Nolte LA, Ju JS, Han DH, Coleman T, Holloszy JO, Semenkovich CF: Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nat Med 2000;6:1115–1120.
50.
Ishigaki Y, Katagiri H, Yamada T, Ogihara T, Imai J, Uno K, Hasegawa Y, Gao J, Ishihara H, Shimosegawa T, Sakoda H, Asano T, Oka Y: Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity. Diabetes 2005;54:322–332.
51.
Brown JE, Thomas S, Digby JE, Dunmore SJ: Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets. FEBS Lett 2002;513:189–192.
52.
Briaud I, Kelpe CL, Johnson LM, Tran PO, Poitout V: Differential effects of hyperlipidemia on insulin secretion in islets of Langerhans from hyperglycemic versus normoglycemic rats. Diabetes 2002;51:662–668.
53.
D’Adamo M, Perego L, Cardellini M, Marini MA, Frontoni S, Andreozzi F, Sciacqua A, Lauro D, Sbraccia P, Federici M, Paganelli M, Pontiroli AE, Lauro R, Perticone F, Folli F, Sesti G: 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.
54.
Bulotta A, Ludovico O, Coco A, Di Paola R, Quattrone A, Carella M, Pellegrini F, Prudente S, Trischitta V: 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. J Clin Endocrinol Metab 2005;90:1176–1180.
55.
Wallace DC: Animal models for mitochondrial disease. Methods Mol Biol 2002;197:3–54.
56.
Oppert JM, Vohl MC, Chagnon M, Dionne FT, Cassard-Doulcier AM, Ricquier D, Perusse L, Bouchard C: DNA polymorphism in the uncoupling protein (UCP) gene and human body fat. Int J Obes Relat Metab Disord 1994;18:526–531.
57.
Herrmann SM, Wang JG, Staessen JA, Kertmen E, Schmidt-Petersen K, Zidek W, Paul M, Brand E: Uncoupling protein 1 and 3 polymorphisms are associated with waist-to-hip ratio. J Mol Med 2003;81:327–332.
58.
Alonso A, Marti A, Corbalan MS, Martinez-Gonzalez MA, Forga L, Martinez JA: Association of UCP3 gene -55C>T polymorphism and obesity in a Spanish population. Ann Nutr Metab 2005;49:183–188.
59.
Rodriguez AM, Palou A: Uncoupling proteins: gender dependence and their relation to body weight control. Int J Obes Relat Metab Disord 2004;28:500–502.
60.
Rodriguez AM, Roca P, Bonet ML, Pico C, Oliver P, Palou A: Positive correlation of skeletal muscle UCP3 mRNA levels with overweight in male, but not in female, rats. Am J Physiol Regul Integr Comp Physiol 2003;285:R880–R888.
61.
Clapham JC, Arch JR, Chapman H, Haynes A, Lister C, Moore GB, Piercy V, Carter SA, Lehner I, Smith SA, Beeley LJ, Godden RJ, Herrity N, Skehel M, Changani KK, Hockings PD, Reid DG, Squires SM, Hatcher J, Trail B, Latcham J, Rastan S, Harper AJ, Cadenas S, Buckingham JA, Brand MD, Abuin A: Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 2000;406:415–418.
62.
Harper ME, Dent R, Monemdjou S, Bezaire V, Van Wyck L, Wells G, Kavaslar GN, Gauthier A, Tesson F, McPherson R: Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women. Diabetes 2002;51:2459–2466.
63.
Kagawa Y, Cha SH, Hasegawa K, Hamamoto T, Endo H: Regulation of energy metabolism in human cells in aging and diabetes: FoF(1), mtDNA, UCP, and ROS.Biochem Biophys Res Commun 1999;266:662–676.
64.
Sullivan PG, Springer JE, Hall ED, Scheff SW: Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr 2004;36:353–356.
65.
Fridell YW, Sanchez-Blanco A, Silvia BA, Helfand SL: Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab 2005;1:145–152.
66.
Mattson MP, Liu D: Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death. Biochem Biophys Res Commun 2003;304:539–549.
67.
Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castillio RF, Melcher T, Gonzalez-Zulueta M, Nikolich K, Wieloch T: Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003;9:1062–1068.
68.
Dejean L, Camara Y, Sibille B, Solanes G, Villarroya F: Uncoupling protein-3 sensitizes cells to mitochondrial-dependent stimulus of apoptosis. J Cell Physiol 2004;201:294–304.
69.
Barazzoni R, Nair KS: Changes in uncoupling protein-2 and -3 expression in aging rat skeletal muscle, liver, and heart. Am J Physiol Endocrinol Metab 2001;280:E413–E419.
70.
Kerner J, Turkaly PJ, Minkler PE, Hoppel CL: Aging skeletal muscle mitochondria in the rat: decreased uncoupling protein-3 content. Am J Physiol Endocrinol Metab 2001;281:E1054–E1062.
71.
Horimoto M, Resnick MB, Konkin TA, Routhier J, Wands JR, Baffy G: Expression of uncoupling protein-2 in human colon cancer. Clin Cancer Res 2004;10:6203–6207.
72.
Nishio K, Qiao S, Yamashita H: Characterization of the differential expression of uncoupling protein 2 and ROS production in differentiated mouse macrophage-cells (Mm1) and the progenitor cells (M1). J Mol Histol 2005;36:35–44.
73.
Carretero MV, Torres L, Latasa U, Garcia-Trevijano ER, Prieto J, Mato JM, Avila MA: Transformed but not normal hepatocytes express UCP2. FEBS Lett 1998;439:55–58.
74.
Jacques C, Baris O, Prunier-Mirebeau D, Savagner F, Rodien P, Rohmer V, Franc B, Guyetant S, Malthiery Y, Reynier P: Two-step differential expression analysis reveals a new set of genes involved in thyroid oncocytic tumors. J Clin Endocrinol Metab 2005;90:2314–2320.
75.
Savagner F, Franc B, Guyetant S, Rodien P, Reynier P, Malthiery Y: Defective mitochondrial ATP synthesis in oxyphilic thyroid tumors. J Clin Endocrinol Metab 2001;86:4920–4925.
76.
Busquets S, Almendro V, Barreiro E, Figueras M, Argiles JM, Lopez-Soriano FJ: Activation of UCPs gene expression in skeletal muscle can be independent on both circulating fatty acids and food intake. Involvement of ROS in a model of mouse cancer cachexia. FEBS Lett 2005;579:717–722.
77.
Collins P, Bing C, McCulloch P, Williams G: Muscle UCP-3 mRNA levels are elevated in weight loss associated with gastrointestinal adenocarcinoma in humans. Br J Cancer 2002;86:372–375.
78.
Bing C, Russell ST, Beckett EE, Collins P, Taylor S, Barraclough R, Tisdale MJ, Williams G: Expression of uncoupling proteins-1, -2 and -3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor. Br J Cancer 2002;86:612–618.
79.
Sanchis D, Busquets S, Alvarez B, Ricquier D, Lopez-Soriano FJ, Argiles JM: Skeletal muscle UCP2 and UCP3 gene expression in a rat cancer cachexia model. FEBS Lett 1998;436:415–418.
80.
DeJong CH, Busquets S, Moses AG, Schrauwen P, Ross JA, Argiles JM, Fearon KC: Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia. Oncol Rep 2005;14:257–263.
81.
Hansen JB, Jorgensen C, Petersen RK, Hallenborg P, De Matteis R, Boye HA, Petrovic N, Enerback S, Nedergaard J, Cinti S: Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc Natl Acad Sci USA 2004;101:4112–4117.
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