Journal of Bioenergetics and Biomembranes

, Volume 31, Issue 5, pp 475–491

UCP1: The Original Uncoupling Protein—and Perhaps the Only One? New Perspectives on UCP1, UCP2, and UCP3 in the Light of the Bioenergetics of the UCP1-Ablated Mice

  • Jan Nedergaard
  • Anita Matthias
  • Valeria Golozoubova
  • Anders Jacobsson
  • Barbara Cannon


The availability of a UCP1-ablated mouse has enabled critical studies of the function of UCP1,UCP2, and UCP3. Concerning UCP1, its presence in brown-fat mitochondria is associatedwith innate uncoupling, high GDP-binding capacity, and GDP-inhibitable Cl- permeabilityand uncoupling—but the high fatty acid sensitivity found in these mitochondria is observedeven in the absence of UCP1. The absence of UCP1 leads to low cold tolerance but not toobesity. UCP1 ablation also leads to an augmented expression of UCP2 and UCP3 in brownadipose tissue, making this tissue probably the one that boasts the highest expression ofthese UCPs. However, these very high expression levels are not associated with any inherentuncoupling, or with a specific GDP-binding capacity, or with a GDP-sensitive Cl- permeability,or with any effect of GDP on mitochondrial membrane potential, or with an increased basalmetabolism of cells, or with the presence of norepinephrine- or fatty acid-induced thermogenesisin cells, and not with a cold-acclimation recruited, norepinephrine-induced thermogenicresponse in the intact animal. Therefore, it can be discussed whether any uncoupling effect isassociated with UCP2 or UCP3 when they are endogenously expressed and, consequently,whether (loss of) uncoupling (thermogenic) effects of UCP2 or UCP3 can be invoked toexplain metabolic phenomena, such as obesity.

Uncoupling proteins nonshivering thermogenesis brown-fat mitochondria liver mitochondria norepinephrine mitochondrial membrane potential obesity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andersson, U., Houstek, J., and Cannon, B. (1997). Biochem. J. 323, 379-385.Google Scholar
  2. Arechaga, I., Raimbault, S., Prieto, S., Levi-Meyrueis, C., Zaragoza, P., Miroux, B., Ricquier, D., Bouillaud, F., and Rial, E. (1993). Biochem. J. 296, 693-700.Google Scholar
  3. Boss, O., Samec, S., Paoloni-Giacobino, A., Rossier, C., Dulloo, A., Seydoux, J., Muzzin, P., and Giacobino, J. P. (1997). FEBS Lett. 408, 39-42.Google Scholar
  4. Boss, O., Muzzin, P., and Giacobino, J.-P. (1998). Eur. J. Endocrinol. 139, 1-9.Google Scholar
  5. Bouillaud, F., Arechaga, I., Petit, P. X., Raimbault, S., Levi-Meyrueis, C., Casteilla, L., Laurent, M., Rial, E., and Ricquier, D. (1994). EMBO J. 13, 1990-7.Google Scholar
  6. Brookes, P. S., Buckingham, J. A., Tenreiro, A. M., Hulbert, A. J., and Brand, M. D. (1998). Comp. Biochem. Physiol. B119, 325-334.Google Scholar
  7. Cadenas, S., Jones, R. B., and Brand, M. D. (1998). Abs. 8th Intern. Congress Obesity, pp. 22-22.Google Scholar
  8. Cannon, B. and Nedergaard, J. (1985). Essays Biochem. 20, 110-164.Google Scholar
  9. Cannon, B., Nicholls, D. G., and Lindberg, O. (1973). In Mechanisms in Bioenergetics(Azzone, G. F. et al., eds.), Academic Press, New York, pp. 357-364.Google Scholar
  10. Cannon, B., Matthias, A., Golozoubova, V., Ohlson, K. B. E., Andersson, U., Jacobsson, A., and Nedergaard, J. (1999). In Progress in Obesity Research 8(Ailhaud, G. and Guy-Grand, B., eds.), John Libbey, London, pp. 13-26.Google Scholar
  11. Champigny, O., and Ricquier, D. (1990). J. Nutr. 120, 1730-1736.Google Scholar
  12. Chavin, K. D., Yang, S., Lin, H. Z., Chatham, J., Chacko, V. P., Hoek, J. B., Walajtys-Rode, E., Rashid, A., Chen, C. H., Huang, C. C., Wu, T. C., Lane, M. D., and Diehl, A. M. (1999). J. Biol. Chem. 274, 5692-5700.Google Scholar
  13. Cortez-Pinto, H., Yang, S. Q., Lin, H. Z., Costa, S., Hwang, C. S., Lane, M. D., Bagby, G., and Diehl, A. M. (1998). Biochem. Biophys. Res. Commun. 251, 313-319.Google Scholar
  14. Enerbäck, S., Jacobsson, A., Simpson, E. M., Guerra, C., Yamashita, H., Harper, M.-E., and Kozak, L. P. (1997). Nature (London) 387, 90-94.Google Scholar
  15. Faggioni, R., Shigenaga, J., Moser, A., Feingold, K. R., and Grunfeld, C. (1998). Biochem. Biophys. Res. Commun. 244, 75-78.Google Scholar
  16. Fleury, C., Levi-Meyrueis, C., Vacher, D., Gonzales-Barroso, M. M., Ricquier, D., Rial, E., and Bouillaud, F. (1997a). In New Perspectives in Mitochondrial Research(Bernardi, P., eds.), Dipartimento de Scienze Biomediche Sperimentali, Padova, pp. C4-C4.Google Scholar
  17. 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. (1997b). Nature Genet. 15, 269-272.Google Scholar
  18. Foster, D. O., and Frydman, M. L. (1978). Can. J. Physiol. Pharmacol. 56, 110-122.Google Scholar
  19. Foster, D. O., and Frydman, M. L. (1979). Can. J. Physiol. Pharmacol. 57, 257-270.Google Scholar
  20. Garlid, K. D., Jaburek, M., and Jezek, P. (1998). FEBS Lett. 438, 10-14.Google Scholar
  21. Gimeno, R. E., Dembski, M., Weng, X., Deng, N., Shyjan, A. W., Gimeno, C. J., Iris, F., Ellis, S. J., Woolf, E. A., and Tartaglia, L. A. (1997). Diabetes 46, 900-906.Google Scholar
  22. Golozoubova, V., Matthias, A., Jacobsson, A., Cannon, B., and Nedergaard, J. (1999). Submitted for publication.Google Scholar
  23. Guerra, C., Koza, R. A., Walsh, K., Kurtz, D. M., Wood, P. A., and Kozak, L. P. (1998). J. Clin. Invest. 102, 1724-1731.Google Scholar
  24. Harper, M. E. and Brand, M.D. (1994) Can. J. Physiol. Pharmacol. 72, 899-908.Google Scholar
  25. Himms-Hagen, J. (1985). Amer. J. Physiol. 248, E531-E539.Google Scholar
  26. Himms-Hagen, J. (1989). Progr. Lipid Res. 28, 67-115.Google Scholar
  27. Hodny, Z., Kolarova, P., Rossmeisl, M., Horakova, M., Nibbelink, M., Penicaud, L., Casteilla, L., and Kopecky, J. (1998). FEBS Lett. 425, 185-190.Google Scholar
  28. Houstek, J., Andersson, U., Tvrdik, P., Nedergaard, J., and Cannon, B. (1995). J. Biol. Chem. 270, 7689-7694.Google Scholar
  29. Jezek, P., and Garlid, K. D. (1990). J. Biol. Chem. 265, 19303-19311.Google Scholar
  30. Kelly, L. J., Vicario, P. P., Thompson, G. M., Candelore, M. R., Doebber, T. W., Ventre, J., Wu, M. S., Meurer, R., Forrest, M. J., Conner, M. W., Cascieri, M. A., and Moller, D. E. (1998). Endocrinology 139, 4920-4927.Google Scholar
  31. Klingenberg, M., and Huang, S. G. (1999). Biochim. Biophys. Acta 1415, 271-296.Google Scholar
  32. Korshunov, S. S., Skulachev, V. P., and Starkov, A. A. (1997). FEBS Lett.15-18.Google Scholar
  33. Kozak, L. P., Kozak, U. C., and Clarke, G. T.(1991). Genes Develop. 5, 2256-2264.Google Scholar
  34. Lanni, A., Beneduce, L., Lombardi, A., Moreno, M., Boss, O., Muzzin, P., Giacobino, J. P. and Goglia, F.(1999). FEBS Lett. 444, 250-254.Google Scholar
  35. Larrouy, D., Laharrague, P., Carrera, G., Viguerie-Bascands, N., Levi-Meyrueis, C., Fleury, C., Pecqueur, C., Nibbelink, M., Andre, M., Casteilla, L., and Ricquier, D. (1997). Biochem. Biophys. Res. Commun. 235, 760-764.Google Scholar
  36. Lee, F. Y., Li, Y., Zhu, H., Yang, S., Lin, H. Z., Trush, M., and Diehl, A. M. (1999). Hepatology 29, 677-87.Google Scholar
  37. Locke, R. M., and Nicholls, D. G.(1981). FEBS Lett. 135, 249-252.Google Scholar
  38. Lowell, B. B., S-Susulic, V., Hamann, A., Lawitts, J. A., Himms-Hagen, J., Boyer, B. B., Kozak, L. P., and Flier, J. S. (1993). Nature (London) 366, 740-742.Google Scholar
  39. Ma, S., Foster, D. O., Nadeau, B. E., and Triandafillou, J. (1988). Can. J. Physiol. Pharmacol. 66, 1347-1354.Google Scholar
  40. Mao, W., Yu, X. X., Zhong, A., Li, W., Brush, J., Sherwood, S. W., Adams, S. H., and Pan, G. (1999). FEBS Lett. 443, 326-330.Google Scholar
  41. Matthias, A., Golozoubova, V., Andersson, U., Jacobsson, A., Cannon, B., and Nedergaard, J. (1999a). Submitted for publication.Google Scholar
  42. Matthias, A., Jacobsson, A., Cannon, B., and Nedergaard, J. (1999b). J. Biol. Chem. 274, 28150-28160.Google Scholar
  43. Matthias, A., Ohlson, K. E. B., Jacobsson, A., Cannon, B., and Nedergaard, J. (1999c). Submitted for publication.Google Scholar
  44. Nedergaard, J., and Cannon, B. (1994). Biochim. Biophys. Acta 1185, 311-317.Google Scholar
  45. Negre-Salvayre, A., Hirtz, C., Carrera, G., Cazenave, R., Troly, M., Salvayre, R., Penicaud, L., and Casteilla, L. (1997). FASEB J. 11, 809-815.Google Scholar
  46. Nicholls, D. G. (1974). Eur. J. Biochem. 49, 585-593.Google Scholar
  47. Nicholls, D. G. (1976a). FEBS Lett. 61, 103-110.Google Scholar
  48. Nicholls, D. G. (1976b). Eur. J. Biochem. 62, 223-228.Google Scholar
  49. Prusiner, S. B., Cannon, B., and Lindberg, O. (1968). Eur. J. Biochem. 6, 15-22.Google Scholar
  50. Rafael, J., Ludolph, H. J., and Hohorst, H. J. (1969). Hoppe Seylers Z. Physiol.Chem. 350, 1121-1131.Google Scholar
  51. Rothwell, N. J., and Stock, M. J. (1979). Nature (London) 281, 31-35.Google Scholar
  52. Sameo, Seydoux, J., and Dulloo, A. G. (1998) FASEB J. 12, 715-724.Google Scholar
  53. 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). J. Biol. Chem. 273, 34611-34615.Google Scholar
  54. Simonyan, R. A., and Skulachev, V. P. (1998). FEBS Lett. 436, 81-84.Google Scholar
  55. Skulachev, V. P. (1991). FEBS Lett. 294, 158-162.Google Scholar
  56. Skulachev, V. P. (1998). Biochim. Biophys. Acta 1363, 100-124.Google Scholar
  57. Strieleman, P. J., Schalinske, K. L., and Shrago, E. (1985). J. Biol. Chem. 260, 13402-13405.Google Scholar
  58. Surwit, R. S., Wang, S., Petro, A. E., Sanchis, D., Raimbault, S., Ricquier, D., and Collins, S. (1998). Proc. Natl. Acad. Sci. USA 95, 4061-4065.Google Scholar
  59. Thomas, S. A., and Palmiter, R. D. (1997). Nature (London)94-97.Google Scholar
  60. Weigle, D. S., Selfridge, L. E., Schwartz, M. W., Seeley, R. J., Cummings, D. E., Havel, P. J., Kuijper, J. L., and Beltrandel-Rio, H. (1998). Diabetes 47, 298-302.Google Scholar
  61. Winkler, E., and Klingenberg, M. (1994). J. Biol. Chem. 269, 2508-2515.Google Scholar
  62. Wojtczak, L., and Schönfeld, P. (1993). Biochim. Biophys. Acta 1183, 41-57.Google Scholar

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Jan Nedergaard
    • 1
  • Anita Matthias
    • 1
  • Valeria Golozoubova
    • 1
  • Anders Jacobsson
    • 1
  • Barbara Cannon
    • 1
  1. 1.The Wenner-Gren Institute, The Arrhenius Laboratories F3Stockholm UniversityStockholmSweden

Personalised recommendations