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Gene Review

Ucp1  -  uncoupling protein 1 (mitochondrial,...

Rattus norvegicus

Synonyms: Mitochondrial brown fat uncoupling protein 1, Slc25a7, Solute carrier family 25 member 7, Thermogenin, UCP 1, ...
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Disease relevance of Ucp1

  • OBJECTIVE: The anti-obesity properties of a new beta3-adrenergic agonist (Trecadrine) were examined in a diet-induced obesity model, including the effects on OB and uncoupling protein (UCP-1 and -2) gene expression [1].
  • By day 20, rats more than doubled food consumption while losing approximately 11% of body weight; metabolism rose to 166% of baseline with substantial increases in UCP1 mRNA and immunoreactive UCP1 over controls; serum leptin decreased and remained suppressed [2].
  • Although UCP1 expression did not alter the sensitivity to ischemia, it significantly improved functional recovery on reperfusion [3].
  • The relative molar expression of these subtypes was quantified through comparison with histidine-tagged UCP1 or UCP2 proteins engineered by expression in Escherichia coli [4].
  • We subjected insulinoma (INS-1) cells to adenoviral expression of UCP2 or UCP1 and assessed the proton leak as the kinetic relationship between oxygen use and the inner mitochondrial membrane potential [4].

Psychiatry related information on Ucp1

  • Chronic REM-sleep deprivation of rats elevates metabolic rate and increases UCP1 gene expression in brown adipose tissue [2].
  • The diminished downregulation of UCP1 and UCP3 expression in BAT by fasting suggests that energy conservation in response to food deprivation is impaired with age, and this may contribute to an inability of older animals to maintain body mass during periods when food is limited [5].

High impact information on Ucp1

  • UCP1 is specific to brown adipose tissue (BAT) whereas UCP2 is expressed in numerous tissues, particularly in monocytes/macrophages [6].
  • Preincubation of BAT mitochondrial fractions with GDP, an inhibitor of UCP1, induced a rise in mitochondrial membrane potential (assessed by rhodamine 123 uptake) and H2O2 production [6].
  • Native uncoupling protein 1 (UCP 1) was purified from rat mitochondria by hydroxyapatite chromatography and identified by peptide mass mapping and tandem mass spectrometry [7].
  • We show that proton flux was greater through native UCP 1-containing proteoliposomes when facilitated by less hydrophilically modified palmitate (palmitate > omega-methoxypalmitate > omega-hydroxypalmitate with little or no proton flux due to glucose-O-omega-palmitate or undecanesulfonate) [7].
  • The abilities of individual UCPs to prevent hyperglycemic PCD were assessed by adenovirus-mediated overexpression of UCP1 and UCP3 [8].

Chemical compound and disease context of Ucp1

  • The decreased expression levels of UCP-1 and its upstream regulators, beta(3)AR and PGC-1, in BAT may contribute to inefficient energy utilization and obesity in OLETF rats, which was corrected by DHEA treatment [9].
  • A dose-dependent reduction in serum insulin levels and unchanged serum glucose, energy expenditure through thermogenesis as indicated by uncoupling protein-1 (UCP-1) mRNA expression in brown adipose tissue (BAT), and metabolism as indicated by serum T3 and T4, accompanied the blockade of weight gain [10].
  • Thus, the findings that estrogen deficiency is followed by reduced UCP1 expression in BAT and reduced UCP2 expression in WAT in association with weight gain probably caused by a decrease in energy expenditure might indicate that UCPs play a role for the estrogen-mediated changes in body weight and energy expenditure [11].
  • The increase in metabolic rate in response to the beta3-agonist CL-316243, was greater in both OM and S5B rats reared at 18 degrees C than in those reared at 30 degrees C. Perinatal temperature differentially affects body weight in OM and S5B rats while having similar effects on food intake, response to a beta3-agonist, and BAT beta3-AR and UCP-1 [12].

Biological context of Ucp1

  • Injection of 0.5 mg/kg risperidone caused a reduction in bodyweight gain, as well as enhanced Ucp1 gene expression in BAT and serum prolactin concentrations [13].
  • To investigate whether fasting affects the expression of UCPs mRNA in brown adipose tissue (BAT) of bilateral ventromedial hypothalamus (VMH)-lesioned rats, we determined the gene expression of UCP1, UCP2 or UCP3 in BAT of VMH-lesioned rats and examined oxygen consumption in these rats under fed or 48-h fasted conditions [14].
  • UCP1 mRNA levels in brown adipose tissue were more elevated during pro-estrus than during metestrus (F = 3.17, p = 0.039) [15].
  • Only plasma leptin levels and expression of UCP1 mRNA are modestly elevated during the estrous cycle in the rat [15].
  • However, the regulation of UCP-3, which is not involved in thermogenesis, seems to differ from UCP-1 given the fact that is not affected by p38MAPK inhibition [16].

Anatomical context of Ucp1

  • The different expression patterns of genes for uncoupling proteins (UCPs) 1, 2 and 3 (ucp1, ucp2 and ucp3) were studied in interscapular brown adipose tissue (BAT) and in four white adipose tissue (WAT) depots (epididymal, inguinal, mesenteric and retroperitoneal) in male rats of different ages (18 days-12 months) [17].
  • Rosiglitazone and retinoic acid induce uncoupling protein-1 (UCP-1) in a p38 mitogen-activated protein kinase-dependent manner in fetal primary brown adipocytes [16].
  • Brown adipose tissue expresses the thermogenic uncoupling protein-1 (UCP-1), which is positively regulated by peroxisome proliferator-activated receptor (PPAR) agonists and retinoids through the activation of the heterodimers PPAR/retinoid X receptor (RXR) and retinoic acid receptor (RAR)/RXR and binding to specific elements in the ucp-1 enhancer [16].
  • First, we compared the effects of fourth and third i.c.v. administration of MTII and found that the hindbrain and forebrain treatments were equally effective at elevating UCP-1 mRNA expression in BAT compared with the respective vehicle-treated group results [18].
  • Taken together, the results indicate that: 1) there is an independent caudal brainstem MC3/4-R trigger for a sympathetically stimulated elevation in BAT UCP-1 gene expression, and 2) the MTII-induced rise in UCP-1 expression can be mediated by circuitry intrinsic to the caudal brainstem and spinal cord [18].

Associations of Ucp1 with chemical compounds

  • Gene expression analysis of leptin and UCP1, 2 and 3 in adipose tissue was not affected by steroid replacement [15].
  • To investigate the mechanism of action of UCP 1, we determined whether hydrophilic modification of the omega-carbon of palmitate effected its transport function [7].
  • The inhibitory effects of PD169316 are mimicked by the antioxidant GSH, suggesting a role for reactive oxygenated species (ROS) generation in the increase of UCP-1 expression in response either to Rosi or 9-cis-retinoic acid [16].
  • Corresponding depot-specific alterations were observed in mRNA levels of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD-1) and the thermogenic modulator uncoupling protein 1 (UCP-1) [19].
  • Quiescent brown preadipocytes express high levels of UCP-1 mRNA in response to triiodothyronine (T3) and norepinephrine (NE) [20].

Regulatory relationships of Ucp1

  • We recently reported that the leptin-induced increase in uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT) is prevented by the denervation of BAT [21].
  • Contrary to uterine UCPs, UCP1 mRNA expression in BAT was down-regulated by 0.5-fold and there were no remarkable changes in WAT or liver UCP2, or Muscle UCP3 expression throughout the periods [22].
  • TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK [23].
  • The present study determines whether maternal administration of prolactin (PRL) to dams promotes the abundance of the brown adipose tissue-specific uncoupling protein-1 (UCP1) in fetal and neonatal rat pups [24].

Other interactions of Ucp1

  • Both ucp1 and ucp3 followed a similar expression pattern with age, with high levels in suckling rats which decreased to 50% or less in rats just under 2 months old, declining thereafter until 5 months and then recovering with age [17].
  • In contrast to ucp1 and ucp3, ucp2 had a peak of expression at about 2 months, and lower expression at 3 months, suggesting different regulation and probably a different role for this UCP [17].
  • These depot-specific effects may be mediated by differential regulation of key metabolic genes, including LPL, 11beta-HSD-1, and UCP-1 [19].
  • BAT UCP1 mRNA expression was increased by 1.2-fold at 6 h after the TNF-alpha treatment and decreased by 0.8-fold at 16 h after the treatment [25].
  • Among the upstream signals for UCP-1 regulation, expression levels of the beta 3 adrenergic receptor (beta(3)AR) and PPAR gamma coactivator-1 (PGC-1) were significantly decreased in the OLETF rats and increased by DHEA administration [9].

Analytical, diagnostic and therapeutic context of Ucp1

  • Leptin, UCP-2 and UCP-1 mRNA levels were assessed by RT-PCR, followed by Southern blot [26].
  • A second experiment demonstrated that the fourth i.c.v. MTII-induced rise in UCP-1 expression was mediated by sympathetic outflow to BAT by showing that this response was abolished by surgical denervation of BAT [18].
  • Uncoupling protein 1 (UCP1), the mammalian thermogenic mitochondrial protein, is found only in brown adipocytes, but its expression by immunohistochemistry is not homogeneous [27].
  • Blood hormones and metabolites were assayed, and expression of uncoupling protein-1 (UCP-1) and hypothalamic energy-balance related genes were determined by Northern blotting or in situ hybridisation, respectively [28].
  • Rats received an intramuscular injection of plasmid pXC1 containing UCP1 cDNA in the right tibialis muscles, while left tibialis muscles were injected with empty plasmid as control [29].


  1. Up-regulation of muscle UCP2 gene expression by a new beta3-adrenoceptor agonist, trecadrine, in obese (cafeteria) rodents, but down-regulation in lean animals. Berraondo, B., Marti, A., Duncan, J.S., Trayhurn, P., Martínez, J.A. Int. J. Obes. Relat. Metab. Disord. (2000) [Pubmed]
  2. Chronic REM-sleep deprivation of rats elevates metabolic rate and increases UCP1 gene expression in brown adipose tissue. Koban, M., Swinson, K.L. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  3. Mitochondrial uncoupling protein 1 expressed in the heart of transgenic mice protects against ischemic-reperfusion damage. Hoerter, J., Gonzalez-Barroso, M.D., Couplan, E., Mateo, P., Gelly, C., Cassard-Doulcier, A.M., Diolez, P., Bouillaud, F. Circulation (2004) [Pubmed]
  4. UCP2-dependent proton leak in isolated mammalian mitochondria. Fink, B.D., Hong, Y.S., Mathahs, M.M., Scholz, T.D., Dillon, J.S., Sivitz, W.I. J. Biol. Chem. (2002) [Pubmed]
  5. Uncoupling proteins 2 and 3 with age: regulation by fasting and beta3-adrenergic agonist treatment. Scarpace, P.J., Kumar, M.V., Li, H., Tümer, N. J. Gerontol. A Biol. Sci. Med. Sci. (2000) [Pubmed]
  6. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. Nègre-Salvayre, A., Hirtz, C., Carrera, G., Cazenave, R., Troly, M., Salvayre, R., Pénicaud, L., Casteilla, L. FASEB J. (1997) [Pubmed]
  7. On the mechanism of mitochondrial uncoupling protein 1 function. Breen, E.P., Gouin, S.G., Murphy, A.F., Haines, L.R., Jackson, A.M., Pearson, T.W., Murphy, P.V., Porter, R.K. J. Biol. Chem. (2006) [Pubmed]
  8. Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death. Vincent, A.M., Olzmann, J.A., Brownlee, M., Sivitz, W.I., Russell, J.W. Diabetes (2004) [Pubmed]
  9. DHEA administration increases brown fat uncoupling protein 1 levels in obese OLETF rats. Ryu, J.W., Kim, M.S., Kim, C.H., Song, K.H., Park, J.Y., Lee, J.D., Kim, J.B., Lee, K.U. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  10. Central LIF gene therapy suppresses food intake, body weight, serum leptin and insulin for extended periods. Beretta, E., Dhillon, H., Kalra, P.S., Kalra, S.P. Peptides (2002) [Pubmed]
  11. Regulation of UCP1, UCP2, and UCP3 mRNA expression in brown adipose tissue, white adipose tissue, and skeletal muscle in rats by estrogen. Pedersen, S.B., Bruun, J.M., Kristensen, K., Richelsen, B. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  12. Effect of a high or low ambient perinatal temperature on adult obesity in Osborne-Mendel and S5B/Pl rats. White, C.L., Braymer, H.D., York, D.A., Bray, G.A. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2005) [Pubmed]
  13. Peripheral injection of risperidone, an atypical antipsychotic, alters the bodyweight gain of rats. Ota, M., Mori, K., Nakashima, A., Kaneko, Y.S., Fujiwara, K., Itoh, M., Nagasaka, A., Ota, A. Clin. Exp. Pharmacol. Physiol. (2002) [Pubmed]
  14. Fasting increases gene expressions of uncoupling proteins and peroxisome proliferator-activated receptor-gamma in brown adipose tissue of ventromedial hypothalamus-lesioned rats. Kageyama, H., Osaka, T., Kageyama, A., Kawada, T., Hirano, T., Oka, J., Miura, M., Namba, Y., Ricquier, D., Shioda, S., Inoue, S. Life Sci. (2003) [Pubmed]
  15. Effects of estrous cycle and steroid replacement on the expression of leptin and uncoupling proteins in adipose tissue in the rat. Luukkaa, V., Savontaus, E., Rouru, J., Virtanen, K.A., Boss, O., Huhtaniemi, I., Koulu, M., Pesonen, U., Huupponen, R. Gynecol. Endocrinol. (2001) [Pubmed]
  16. Rosiglitazone and retinoic acid induce uncoupling protein-1 (UCP-1) in a p38 mitogen-activated protein kinase-dependent manner in fetal primary brown adipocytes. Teruel, T., Hernandez, R., Benito, M., Lorenzo, M. J. Biol. Chem. (2003) [Pubmed]
  17. Differential expression of genes for uncoupling proteins 1, 2 and 3 in brown and white adipose tissue depots during rat development. Oliver, P., Picó, C., Palou, A. Cell. Mol. Life Sci. (2001) [Pubmed]
  18. Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat. Williams, D.L., Bowers, R.R., Bartness, T.J., Kaplan, J.M., Grill, H.J. Endocrinology (2003) [Pubmed]
  19. PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion. Laplante, M., Sell, H., MacNaul, K.L., Richard, D., Berger, J.P., Deshaies, Y. Diabetes (2003) [Pubmed]
  20. Growth factor regulation of uncoupling protein-1 mRNA expression in brown adipocytes. García, B., Obregón, M.J. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  21. Modulation of uncoupling protein 2 and uncoupling protein 3: regulation by denervation, leptin and retinoic acid treatment. Scarpace, P.J., Matheny, M., Moore, R.L., Kumar, M.V. J. Endocrinol. (2000) [Pubmed]
  22. Up-regulation of uterine UCP2 and UCP3 in pregnant rats. Masaki, T., Yoshimatsu, H., Chiba, S., Kurokawa, M., Sakata, T. Biochim. Biophys. Acta (1999) [Pubmed]
  23. TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK. Valladares, A., Roncero, C., Benito, M., Porras, A. FEBS Lett. (2001) [Pubmed]
  24. The effect of maternal prolactin infusion during pregnancy on fetal adipose tissue development. Budge, H., Mostyn, A., Wilson, V., Khong, A., Walker, A.M., Symonds, M.E., Stephenson, T. J. Endocrinol. (2002) [Pubmed]
  25. Tumor necrosis factor-alpha regulates in vivo expression of the rat UCP family differentially. Masaki, T., Yoshimatsu, H., Chiba, S., Hidaka, S., Tajima, D., Kakuma, T., Kurokawa, M., Sakata, T. Biochim. Biophys. Acta (1999) [Pubmed]
  26. Pancreastatin, a chromogranin A-derived peptide, inhibits leptin and enhances UCP-2 expression in isolated rat adipocytes. González-Yanes, C., Sánchez-Margalet, V. Cell. Mol. Life Sci. (2003) [Pubmed]
  27. CL316,243 and cold stress induce heterogeneous expression of UCP1 mRNA and protein in rodent brown adipocytes. Cinti, S., Cancello, R., Zingaretti, M.C., Ceresi, E., De Matteis, R., Giordano, A., Himms-Hagen, J., Ricquier, D. J. Histochem. Cytochem. (2002) [Pubmed]
  28. Introduction of a high-energy diet acutely up-regulates hypothalamic cocaine and amphetamine-regulated transcript, Mc4R and brown adipose tissue uncoupling protein-1 gene expression in male Sprague-Dawley rats. Archer, Z.A., Rayner, D.V., Duncan, J.S., Bell, L.M., Mercer, J.G. J. Neuroendocrinol. (2005) [Pubmed]
  29. UCP1 muscle gene transfer and mitochondrial proton leak mediated thermogenesis. Larrarte, E., Margareto, J., Novo, F.J., Marti, A., Alfredo Martínez, J. Arch. Biochem. Biophys. (2002) [Pubmed]
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