• 1
    Nicholls, D. G., and Locke, R. M. ( 1984) Thermogenic mechanisms in brown fat. Physiol. Rev. 64, 164.
  • 2
    Ricquier, D., and Kader, J. C. ( 1976) Mitochondrial protein alteration in active brown fat: a soidum dodecyl sulfate-polyacrylamide gel electrophoretic study. Biochem. Biophys. Res. Commun. 73, 577583.
  • 3
    Enerback, S.,Jacobsson, A.,Simpson, E. M.,Guerra, C.,Yamashita, H.,Harper, M. E., and Kozak, L. P. ( 1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 9094.
  • 4
    Rial, E., and Nicholls, D. G. ( 1983) The regulation of the proton conductance of brown fat mitochondria. Identification of functional and non-functional nucleotide-binding sites. FEBS Lett. 161, 284288.
  • 5
    Cassard-Doulcier, A. M.,Gelly, C.,Fox, N.,Schrementi, J.,Raimbault, S.,Klaus, S.,Forest, C.,Bouillaud, F., and Ricquier, D. ( 1993) Tissue-specific and beta-adrenergic regulation of the mitochondrial uncoupling protein gene: control by cis-acting elements in the 5′-flanking region. Mol. Endocrinol. 7, 497506.
  • 6
    Garlid, K. D.,Orosz, D. E.,Modriansky, M.,Vassanelli, S., and Jezek, P. ( 1996) On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J. Biol. Chem. 271, 26152620.
  • 7
    Gonzalez-Barroso, M. M.,Fleury, C.,Bouillaud, F.,Nicholls, D. G., and Rial, E. ( 1998) The uncoupling protein UCPl does not increase the proton conductance of the inner mitochondrial membrane by functioning as a fatty acid anion transporter. J. Biol. Chem. 273, 1552815532.
  • 8
    Boss, O.,Samec, S.,Paoloni-Giacobino, A.,Rossier, C.,Dulloo, A.,Seydoux, J.,Muzzin, P., and Giacobino, J. P. ( 1997) Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 408, 3942.
  • 9
    Fleury, C.,Neverova, M.,Collins, S.,Raimbault, S.,Champigny, O.,Levi-Meyrueis, C.,Bouillaud, F.,Seldin, M. F.,Surwit, R. S.,Ricquier, D., and Warden, C. H. ( 1997) Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat. Genet. 15, 269272.
  • 10
    Mao, W.,Yu, X. X.,Zhong, A.,Li, W.,Brush, J.,Sherwood, S. W.,Adams, S. H., and Pan, G. ( 1999) UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett. 443, 326330.
  • 11
    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., and Ricquier, D. ( 1998) 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. 273, 3461134615.
  • 12
    Bouillaud, F.,Ricquier, D.,Mory, G., and Thibault, J. ( 1984) Increased level of mRNA for the uncoupling protein in brown adipose tissue of rats during thermogenesis induced by cold exposure or norepinephrine infusion. J. Biol. Chem. 259, 1158311586.
  • 13
    Medvedev, A. V.,Robidoux, J.,Bai, X.,Cao, W.,Floering, L. M.,Daniel, K. W., and Collins, S. ( 2002) Regulation of the uncoupling protein-2 gene in INS-1 beta-cells by oleic acid. J. Biol. Chem. 277, 4263942644.
  • 14
    Kageyama, H.,Osaka, T.,Kageyama, A.,Kawada, T.,Hirano, T.,Oka, J.,Miura, M.,Namba, Y.,Ricquier, D.,Shioda, S., and Inoue, S. ( 2003) Fasting increases gene expressions of uncoupling proteins and peroxisome proliferator-activated receptor-gamma in brown adipose tissue of ventromedial hypothalamus-lesioned rats. Life Sci. 72, 30353046.
  • 15
    Oberkofler, H.,Klein, K.,Felder, T. K.,Krempler, F., and Patsch, W. ( 2006) Role of peroxisome proliferator-activated receptor-gamma coactivator-1 aIpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells. Endocrinology 147, 966976.
  • 16
    Bordone, L.,Motta, M. C.,Picard, F.,Robinson, A.,Jhala, U. S.,Apfeld, J.,McDonagh, T.,Lemieux, M.,McBurney, M.,Szilvasi, A.,Easlon, E. J.,Lin, S. J., and Guarente, L. ( 2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 4, e31.
  • 17
    Pecqueur, C.,Alves-Guerra, M. C.,Gelly, C.,Levi-Meyrueis, C.,Couplan, E.,Collins, S.,Ricquier, D.,Bouillaud, F., and Miroux, B. ( 2001) Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J. Biol. Chem. 276, 87058712.
  • 18
    Hurtaud, C.,Gelly, C.,Bouillaud, F., and Levi-Meyrueis, C. ( 2006) Translation control of UCP2 synthesis by the upstream open reading frame. Cell. Mol. Life Sci. 63, 17801789.
  • 19
    Hurtaud, C.,Gelly, C.,Chen, Z.,Levi-Meyrueis, C., and Bouillaud, F. ( 2007) Glutamine stimulates translation of uncoupling protein 2mRNA. Cell. Mol. Life Sci. 64, 18531860.
  • 20
    Rousset, S.,Mozo, J.,Dujardin, G.,Emre, Y.,Masscheleyn, S.,Ricquier, D., and Cassard-Doulcier, A. M. ( 2007) UCP2 is a mitochondrial transporter with an unusual very short half-life. FEBS Lett. 581, 479482.
  • 21
    Zhang, C. Y.,Baffy, G.,Perret, P.,Krauss, S.,Peroni, O.,Grujic, D.,Hagen, T.,Vidal-Puig, A. J.,Boss, O.,Kim, Y. B.,Zheng, X. X.,Wheeler, M. B.,Shulman, G. I.,Chan, C. B., and Lowell, B. B. ( 2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105, 745755.
  • 22
    Arsenijevic, D.,Onuma, H.,Pecqueur, C.,Raimbault, S.,Manning, B. S.,Miroux, B.,Couplan, E.,Alves-Guerra, M. C.,Goubern, M.,Surwit, R.,Bouillaud, F.,Richard, D.,Collins, S., and Ricquier, D. ( 2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet. 26, 435439.
  • 23
    Vogler, S.,Pahnke, J.,Rousset, S.,Ricquier, D.,Moch, H.,Miroux, B., and Ibrahim, S. M. ( 2006) Uncoupling protein 2 has protective function during experimental autoimmune encephalomyelitis. Am. J. Pathol. 168, 15701575.
  • 24
    Blanc, J.,Alves-Guerra, M. C.,Esposito, B.,Rousset, S.,Gourdy, P.,Ricquier, D.,Tedgui, A.,Miroux, B., and Mallat, Z. ( 2003) Protective role of uncoupling protein 2 in atherosclerosis. Circulation 107, 388390.
  • 25
    Moukdar, F.,Robidoux, J.,Lyght, O.,Pi, J.,Daniel, K. W., and Collins, S. ( 2009) Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice. J. Lipid. Res. 50, 5970.
  • 26
    Emre, Y.,Hurtaud, C.,Karaca, M.,Nubel, T.,Zavala, F., and Ricquier, D. ( 2007) Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes. Proc. Natl. Acad. Sci. USA 104, 1908519090.
  • 27
    de Bilbao, F.,Arsenijevic, D.,Vallet, P.,Hjelle, O. P.,Ottersen, O. P.,Bouras, C.,Raffin, Y.,Abou, K.,Langhans, W.,Collins, S.,Plamondon, J.,Alves-Guerra, M. C.,Haguenauer, A.,Garcia, I.,Richard, D.,Ricquier, D., and Giannakopoulos, P. ( 2004) Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels. J. Neurochem. 89, 12831292.
  • 28
    Diano, S.,Matthews, R. T.,Patrylo, P.,Yang, L.,Beal, M. F.,Barnstable, C. J., and Horvath, T. L. ( 2003) Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144, 50145021.
  • 29
    Mattiasson, G.,Shamloo, M.,Gido, G.,Mathi, K.,Tomasevic, G.,Yi, S.,Warden, C. H.,Castilho, R. F.,Melcher, T.,Gonzalez-Zulueta, M.,Nikolich, K., and Wieloch, T. ( 2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat. Med. 9, 10621068.
  • 30
    Zhang, C. Y.,Parton, L. E.,Ye, C. P.,Krauss, S.,Shen, R.,Lin, C. T.,Porco, J. A.,Jr., and Lowell, B. B. ( 2006) Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell. Metab. 3, 417427.
  • 31
    Bai, Y.,Onuma, H.,Bai, X.,Medvedev, A. V.,Misukonis, M.,Weinberg, J. B.,Cao, W.,Robidoux, J.,Floering, L. M.,Daniel, K. W., and Collins, S. ( 2005) Persistent nuclear factor-kappa B activation in Ucp2−/− mice leads to enhanced nitric oxide and inflammatory cytokine production. J. Biol. Chem. 280, 1906219069.
  • 32
    Rolfe, D. F.,Hulbert, A. J., and Brand, M. D. ( 1994) Characteristics of mitochondrial proton leak and control of oxidative phosphorylation in the major oxygen-consuming tissues of the rat. Biochim. Biophys. Acta 1188, 405416.
  • 33
    Stuart, J. A.,Harper, J. A.,Brindle, K. M.,Jekabsons, M. B., and Brand, M. D. ( 2001) A mitochondrial uncoupling artifact can be caused by expression of uncoupling protein 1 in yeast. Biochem. J. 356, 779789.
  • 34
    Harper, J. A.,Stuart, J. A.,Jekabsons, M. B.,Roussel, D.,Brindle, K. M.,Dickinson, K.,Jones, R. B., and Brand, M. D. ( 2002) Artifactual uncoupling by uncoupling protein 3 in yeast mitochondria at the concentrations found in mouse and rat skeletal-muscle mitochondria. Biochem. J. 361, 4956.
  • 35
    Couplan, E.,del Mar Gonzalez-Barroso, M.,Alves-Guerra, M. C.,Ricquier, D.,Goubern, M., and Bouillaud, F. ( 2002) No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria. J. Biol. Chem. 277, 2626826275.
  • 36
    Boss, O.,Hagen, T., and Lowell, B. B. ( 2000) Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metalmlism. Diabetes 49, 143156.
  • 37
    Samec, S.,Seydoux, J., and Dulloo, A. G. ( 1998) Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate? FASEB J. 12, 715724.
  • 38
    Simoneau, J. A.,Kelley, D. E.,Neverova, M., and Warden, C. H. ( 1998) Overexpression of muscle uncoupling protein 2 content in human obesity associates with reduced skeletal muscle lipid utilization. FASEB J. 12, 17391745.
  • 39
    Pecqueur, C.,Bui, T.,Gelly, C.,Hauchard, J.,Barbot, C.,Bouillaud, F.,Ricquier, D.,Miroux, B., and Thompson, C. B. ( 2008) Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization. FASEB J. 22, 918.
  • 40
    Nedergaard, J., and Cannon, B. ( 2003) The ‘novel’ ‘uncoupling’ proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Exp. Physiol. 88, 6584.
  • 41
    Parton, L. E.,Ye, C. P.,Coppari, R.,Enriori, P. J.,Choi, B.,Zhang, C. Y.,Xu, C.,Vianna, C. R.,Balthasar, N.,Lee, C. E.,Elmquist, J. K.,Cowley, M. A., and Lowell, B. B. ( 2007) Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228232.
  • 42
    Nubel, T.,Emre, Y.,Rabier, D.,Chadefaux, B.,Ricquier, D., and Bouillaud, F. ( 2008) Modified glutamine catabolism in macrophages of Ucp2 knock-out mice. Biochim. Biophys. Acta. 1777, 4854.
  • 43
    Newsholme, P.,Gordon, S., and Newsholme, E. A. ( 1987) Rates of utilization and fares of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages. Biochem. J. 242, 631636.
  • 44
    Curi, T. C.,De Melo, M. P.,De Azevedo, R. B.,Zorn, T. M., and Curi, R. ( 1997) Glutamine utilization by rat neutrophils: presence of phosphate-dependent glutaminase. Am. J. Physiol. 273, C1124C1129.
  • 45
    Moreno-Sanchez, R.,Rodriguez-Enriquez, S.,Marin-Hernandez, A., and Saavedra, E. ( 2007) Energy metabolism in tumor cells. FEBS J. 274, 13931418.
  • 46
    Derdak, Z.,Fulop, P.,Sabo, E.,Tavares, R.,Berthiaume, E. P.,Resnick, M. B.,Paragh, G.,Wands, J. R., and Baffy, G. ( 2006) Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis 27, 956961.
  • 47
    Samudio, I.,Fiegl, M.,McQueen, T.,Clise-Dwyer, K., and Andreeff, M. ( 2008) The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res. 68, 51985205.
  • 48
    Horimoto, M.,Resnick, M. B.,Konkin, T. A.,Routhier, J.,Wands, J. R., and Baffy, G. ( 2004) Expression of uncoupling protein-2 in human colon cancer. Clin. Cancer Res. 10, 62036207.
  • 49
    Gatenby, R. A., and Gillies, R. J. ( 2004) Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891899.
  • 50
    Jezek, P., and Borecky, J. ( 1998) Mitochondrial uncoupling protein may participate in futile cycling of pyruvate and other monocarboxylates. Am. J. Physiol. 275, C496504.
  • 51
    Jezek, P., and Garlid, K. D. ( 1990) New substrates and competitive inhibitors of the Cl-translocating pathway of the uncoupling protein of brown adipose tissue mitochondria. J. Biol. Chem. 265, 1930319311.
  • 52
    Curi, R.,Newsholme, P., and Newsholme, E. A. ( 1988) Metabolism of pyruvate by isolated rat mesenteric lymphocytes, lymphocyte mitochondria and isolated mouse macrophages. Biochem. J. 250, 383388.
  • 53
    Melov, S.,Coskun, P.,Patel, M.,Tuinstra, R.,Cottrell, B.,Jun, A. S.,Zastawny, T. H.,Dizdaroglu, M.,Goodman, S. I.,Huang, T. T.,Miziorko, H.,Epstein, C. J., and Wallace, D. C. ( 1999) Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc. Natl. Acad. Sci. USA 96, 846851.
  • 54
    Forman, H. J., and Torres, M. ( 2001) Signaling by the respiratory burst in macrophages. IUBMB Life 51, 365371.
  • 55
    Kakei, M.,Kelly, R. P.,Ashcroft, S. J., and Ashcroft, F. M. ( 1986) The ATP- sensitivity of K+ channels in rat pancreatic B-cells is modulated by ADP. FEBS Lett. 208, 6366.
  • 56
    Lopaschuk, G. D., and Stanley, W. C. ( 1997) Glucose metabolism in the ischemic heart. Circulation 95, 313315.