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Gene Review

Ucp2  -  uncoupling protein 2 (mitochondrial,...

Mus musculus

Synonyms: Mitochondrial uncoupling protein 2, Slc25a8, Solute carrier family 25 member 8, UCP 2, UCPH
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Disease relevance of Ucp2


Psychiatry related information on Ucp2


High impact information on Ucp2

  • The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3) [1].
  • Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS) [1].
  • We show here that PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs) [7].
  • This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion [5].
  • Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak [5].

Chemical compound and disease context of Ucp2


Biological context of Ucp2

  • Thus, the mere observation of a high level of Ucp2 or Ucp3 mRNA in a tissue cannot be taken as an indication that mitochondria isolated from that tissue will display innate de-energization or thermogenesis [12].
  • One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2-/-) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms [13].
  • Upregulation of pro-inflammatory cytokines IFNgamma, IL6, and IL1beta and of the chemokine MCP1 was observed in Ucp2(-/-) mice 4 days after infection, preceded by a decrease of the anti-inflammatory cytokine IL10 production [14].
  • Hence, chronically, ghrelin controls glucose homeostasis by regulating pancreatic Ucp2 expression and insulin sensitivity [15].
  • We believe that the mild obesity found in Y1-R-/- mice (especially females) was caused by the impaired control of insulin secretion and/or low energy expenditure, including the lowered expression of UCP2 in WAT [16].

Anatomical context of Ucp2


Associations of Ucp2 with chemical compounds


Regulatory relationships of Ucp2

  • These results suggest that the UCP2 protein of the undifferentiated cell is regulated at a quite low level and the higher UCP2 protein of the differentiated macrophages involves with the regulation of ROS production [24].
  • We conclude that mitochrondrially derived reactive oxygen from Ucp2-/- cells constitutively activates NF-kappa B, resulting in a "primed" state to both potentiate and amplify the inflammatory response upon subsequent stimulation [13].
  • Persistent nuclear factor-kappa B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production [13].
  • Mechanism for peroxisome proliferator-activated receptor-alpha activator-induced up-regulation of UCP2 mRNA in rodent hepatocytes [22].
  • Experiments performed in differentiated 3T3F442A preadipocytes showed that TNF-alpha (10 ng/ml) induced a reduction of UCP-2 trancripts, assessed by Northern blot analysis [25].

Other interactions of Ucp2

  • To unmask the effects of absent leptin and its potential proinflammatory actions, steatosis was also induced in UCP2-/- mice by a high-fat diet continued for 6 months [2].
  • In contrast, cardiac UCP-2 expression is regulated in part by a fatty acid-dependent, PPARalpha-independent mechanism [26].
  • The Ucp2 and Ucp3 mRNA levels were therefore among the highest found in any tissue [12].
  • We further demonstrate that ablation of ghrelin reduces expression of Ucp2 mRNA in the pancreas, which contributes toward enhanced glucose-induced insulin secretion [15].
  • Mm1 cells have a high ability of phagocytosis along with significantly high levels of reactive oxygen species (ROS) production, UCP2 protein and manganese superoxide dismutase (Mn-SOD), in contrast to undifferentiated leukemia cells (M1) [24].

Analytical, diagnostic and therapeutic context of Ucp2


  1. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. 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., Ricquier, D. Nat. Genet. (2000) [Pubmed]
  2. Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. Baffy, G., Zhang, C.Y., Glickman, J.N., Lowell, B.B. Hepatology (2002) [Pubmed]
  3. Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia. Bing, C., Brown, M., King, P., Collins, P., Tisdale, M.J., Williams, G. Cancer Res. (2000) [Pubmed]
  4. Barbara Cannon's data on the UCP1-ablated mice: "non-cannonical" point of view. Skulachev, V.P. Biosci. Rep. (2001) [Pubmed]
  5. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. Krauss, S., Zhang, C.Y., Scorrano, L., Dalgaard, L.T., St-Pierre, J., Grey, S.T., Lowell, B.B. J. Clin. Invest. (2003) [Pubmed]
  6. Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold. Horvath, B., Spies, C., Horvath, G., Kox, W.J., Miyamoto, S., Barry, S., Warden, C.H., Bechmann, I., Diano, S., Heemskerk, J., Horvath, T.L. Biochem. Pharmacol. (2002) [Pubmed]
  7. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R.C., Spiegelman, B.M. Cell (1999) [Pubmed]
  8. Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression. Fülöp, P., Derdák, Z., Sheets, A., Sabo, E., Berthiaume, E.P., Resnick, M.B., Wands, J.R., Paragh, G., Baffy, G. Hepatology (2006) [Pubmed]
  9. Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels. 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., Giannakopoulos, P. J. Neurochem. (2004) [Pubmed]
  10. Uncoupling protein-2 promotes nigrostriatal dopamine neuronal function. Andrews, Z.B., Rivera, A., Elsworth, J.D., Roth, R.H., Agnati, L., Gago, B., Abizaid, A., Schwartz, M., Fuxe, K., Horvath, T.L. Eur. J. Neurosci. (2006) [Pubmed]
  11. Estrogen reduces the severity of autonomic dysfunction in spinal cord-injured male mice. Webb, A.A., Chan, C.B., Brown, A., Saleh, T.M. Behav. Brain Res. (2006) [Pubmed]
  12. The bioenergetics of brown fat mitochondria from UCP1-ablated mice. Ucp1 is not involved in fatty acid-induced de-energization ("uncoupling"). Matthias, A., Jacobsson, A., Cannon, B., Nedergaard, J. J. Biol. Chem. (1999) [Pubmed]
  13. Persistent nuclear factor-kappa B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production. Bai, Y., Onuma, H., Bai, X., Medvedev, A.V., Misukonis, M., Weinberg, J.B., Cao, W., Robidoux, J., Floering, L.M., Daniel, K.W., Collins, S. J. Biol. Chem. (2005) [Pubmed]
  14. The uncoupling protein 2 modulates the cytokine balance in innate immunity. Rousset, S., Emre, Y., Join-Lambert, O., Hurtaud, C., Ricquier, D., Cassard-Doulcier, A.M. Cytokine (2006) [Pubmed]
  15. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Sun, Y., Asnicar, M., Saha, P.K., Chan, L., Smith, R.G. Cell metabolism. (2006) [Pubmed]
  16. Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. Kushi, A., Sasai, H., Koizumi, H., Takeda, N., Yokoyama, M., Nakamura, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  17. No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria. Couplan, E., del Mar Gonzalez-Barroso, M., Alves-Guerra, M.C., Ricquier, D., Goubern, M., Bouillaud, F. J. Biol. Chem. (2002) [Pubmed]
  18. Uncoupling protein 2, but not uncoupling protein 1, is expressed in the female mouse reproductive tract. Rousset, S., Alves-Guerra, M.C., Ouadghiri-Bencherif, S., Kozak, L.P., Miroux, B., Richard, D., Bouillaud, F., Ricquier, D., Cassard-Doulcier, A.M. J. Biol. Chem. (2003) [Pubmed]
  19. Kainic acid upregulates uncoupling protein-2 mRNA expression in the mouse brain. Clavel, S., Paradis, E., Ricquier, D., Richard, D. Neuroreport (2003) [Pubmed]
  20. Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty scid-induced thermogenesis. Matthias, A., Ohlson, K.B., Fredriksson, J.M., Jacobsson, A., Nedergaard, J., Cannon, B. J. Biol. Chem. (2000) [Pubmed]
  21. Up-regulation of liver uncoupling protein-2 mRNA by either fish oil feeding or fibrate administration in mice. Tsuboyama-Kasaoka, N., Takahashi, M., Kim, H., Ezaki, O. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  22. Mechanism for peroxisome proliferator-activated receptor-alpha activator-induced up-regulation of UCP2 mRNA in rodent hepatocytes. Nakatani, T., Tsuboyama-Kasaoka, N., Takahashi, M., Miura, S., Ezaki, O. J. Biol. Chem. (2002) [Pubmed]
  23. Increased infarct size and lack of hyperphagic response after focal cerebral ischemia in peroxisome proliferator-activated receptor beta-deficient mice. Arsenijevic, D., de Bilbao, F., Plamondon, J., Paradis, E., Vallet, P., Richard, D., Langhans, W., Giannakopoulos, P. J. Cereb. Blood Flow Metab. (2006) [Pubmed]
  24. Characterization of the differential expression of uncoupling protein 2 and ROS production in differentiated mouse macrophage-cells (Mm1) and the progenitor cells (M1). Nishio, K., Qiao, S., Yamashita, H. J. Mol. Histol. (2005) [Pubmed]
  25. Nitric oxide-dependent downregulation of adipocyte UCP-2 expression by tumor necrosis factor-alpha. Merial, C., Bouloumie, A., Trocheris, V., Lafontan, M., Galitzky, J. Am. J. Physiol., Cell Physiol. (2000) [Pubmed]
  26. Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. Young, M.E., Patil, S., Ying, J., Depre, C., Ahuja, H.S., Shipley, G.L., Stepkowski, S.M., Davies, P.J., Taegtmeyer, H. FASEB J. (2001) [Pubmed]
  27. Mechanism of ubiquitous expression of mouse uncoupling protein 2 mRNA: control by cis-acting DNA element in 5'-flanking region. Yoshitomi, H., Yamazaki, K., Tanaka, I. Biochem. J. (1999) [Pubmed]
  28. Lipids up-regulate uncoupling protein 2 expression in rat hepatocytes. Cortez-Pinto, H., Zhi Lin, H., Qi Yang, S., Odwin Da Costa, S., Diehl, A.M. Gastroenterology (1999) [Pubmed]
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