线粒体解偶联蛋白3的生理作用及影响其表达因素的研究
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摘要
目的：研究C2C12细胞超表达UCP3及共超表达CPT1对脂肪酸氧化、活性氧产生和胰岛素敏感性的影响,以及脂肪酸、WY14643、亮氨酸和AICAR对UCP3表达的影响。
方法：(1)UCP3和CPT1重组腺病毒感染C2C12细胞后测试油酸氧化速率和2-脱氧葡萄糖摄取速率及活性氧产生水平；(2)不同物质干预C2C12细胞后,实时荧光定量PCR测试UCP3mRNA表达水平。
结果：(1)与GFP相比,感染UCP3组、CPTla组及共感染UCP3和CPTla组,脂肪酸氧化增加62.8%(P<0.01),80.2%(P<0.001)、168.4%(P<0.001),与感染UCP3组、CPTla组和共感染UCP3和GFP组比,共感染UCP3和CPTla组脂肪酸氧化增加64.8%(P<0.001)、48.9%(P<0.001)、63.0%(P<0.001)；(2)在没有肉碱或含有爱克莫舍时,感染UCP3组脂肪氧化下降39.6%(P<0.05)、43.8%(P<0.01)；(3)感染UCP3组、CPTla组及共感染UCP3和CPTla组在施加胰岛素后比GFP组2-脱氧葡萄糖摄取速率增加25.8%(P<0.01)、13.3%(P<0.05)及21.8%(P<0.05)；(4)感染UCP3组、CPTla组及共感染UCP3和CPTla组比感染GFP组活性氧生成增加39.3%(P<0.01),54.1%(P<0.001)及53.7%(P<0.001)；(5)与0.75mM辛酸相比,0.75mM油酸组UCP3 mRNA增加117.9%(P<0.001)；(6)与丙氨酸相比,WY14643、亮氨酸以及亮氨酸和WY14643共同干预组,UCP3 mRNA表达分别增加63.2%(P<0.001)、41.0%(P<0.01)以及66.7%(P<0.001)。(7)AICAR干预2小时后,UCP3 mRNA表达水平增加(P<0.001)。
结论：超表达UCP3能增加脂肪酸氧化水平和胰岛素敏感性,但没有减少活性氧产生；CPT1具有协同促进UCP3增加脂肪酸氧化水平的作用；长链脂肪酸能增加UCP3表达但中链脂肪酸对其没有影响；WY14643、亮氨酸和短时间AICAR干预能增加UCP3表达。
Purpose:To study the effect of overexpression of UCP3 in C2C12 myotubes on fatty acid oxidation and the production of reactive oxygen species, especially under the condition of co-overexpression of CPT1. And to study the effect of fatty acids, WY14643, leucine and AICAR on the expression of UCP3.
Methods:(1) To examine oleic acid oxidation rate and 2-deoxyglucose uptake rate by isotope method and to examine the production of superoxide by DHE fluorescence probe in C2C12 myotubes which were infected with UCP3 recombinant adenovirus and CPTla recombinant adenovirus which were prepared by cloning technique. (2) To examine the expression of UCP3 mRNA by real time RT-PCR in in C2C12 myotubes which are treated with fatty acids, WY14643, leucine and AICAR.
Results:(1) Fatty acid oxidation was significantly increased by 62.8%(P< 0.01),80.2%(P< 0.001) respectively after infected with Adv-UCP3, Adv-CPTla, and increased by 168.4%(P<0.001) when co-infected cells with Adv-UCP3 and Adv-CPTla compared with corresponding Adv-GFP-infected myotubes. And more interestingly, fatty acid oxidation was markedly increased by 64.8%(P<0.001),48.9%(P<0.001),63.0%(P <0.001) when co-infected with Adv-UCP3 and Adv-CPTla compared with Adv-UCP3, Adv-CPTla, co-Adv-UCP3-Adv-GFP infected myotubes respectively. (2) Furthermore, fatty acid oxidation was reduced by 39.6%(P<0.05) and 43.8%(P<0.01) respectively in the absence of carnitine (activator of CPT1) and in the presence of etomoxir (inhibitor of CPT1) even upregulated expression of UCP3. (3) 2-deoxyglucose uptake was significantly increased by 25.8%(P<0.01),13.3%(P<0.05) and 21.8% (P<0.05) respectively after infected with Adv-UCP3, Adv-CPTla, and co-infected with Adv-UCP3 and Adv-CPTla compared with corresponding Adv-GFP infected myotubes under the treatment of insulin. (4) On the other hand, over-expression of UCP3 and CPTla in C2C12 myotubes also increased the production of reactive oxygen species by 39.3%(P<0.01),54.1%(P < 0.001)after infected with Adv-UCP3, Adv-CPTla, and increased by 53.7%(P<0.001) when co-infected Adv-UCP3 with Adv-CPTla. (5) UCP3 mRNA and CPT1a mRNA were increased by 117.9% (P<0.001) and 117.2%(P<0.001) respectively compared with the treatment of 0.75mM caprylic acid. (6) Compared with the treatment of alanine, UCP3 mRNA was increased by 63.2%(P <0.001),41.0%(P<0.01) and 66.7%(P<0.001) and fatty acid oxidation was increased by 23.2%(P<0.01),21.2%(P<0.001) and 35.7%(P<0.001) under the treatment of WY14643 (agonist of PPAR a), leucine and co-treatment of WY14643 and leucine respectively. (7) UCP3 mRNA and fatty acid oxidation were increased significantly (P<0.001) after 2 hours under the treatment of AICAR, but UCP3 mRNA was not changeable after 6 hours and 24 hours treatment of AICAR.
Conclusion:Overexpression of UCP3 may significantly increase fatty acid oxidation and insulin sensitivity, but don't decrease the production of reactive oxygen species. CPT1 promote the effect of UCP3 on increasing fatty acid oxidation.long-chain fatty acid but not medium-chain fatty acid increased the expression of UCP3. WY14643 and leucine increased the expression of UCP3 and the capacity of fatty acid oxidation while AICAR involve in this role at the early stage of its treatment.
方法：(1)UCP3和CPT1重组腺病毒感染C2C12细胞后测试油酸氧化速率和2-脱氧葡萄糖摄取速率及活性氧产生水平；(2)不同物质干预C2C12细胞后,实时荧光定量PCR测试UCP3mRNA表达水平。
结果：(1)与GFP相比,感染UCP3组、CPTla组及共感染UCP3和CPTla组,脂肪酸氧化增加62.8%(P<0.01),80.2%(P<0.001)、168.4%(P<0.001),与感染UCP3组、CPTla组和共感染UCP3和GFP组比,共感染UCP3和CPTla组脂肪酸氧化增加64.8%(P<0.001)、48.9%(P<0.001)、63.0%(P<0.001)；(2)在没有肉碱或含有爱克莫舍时,感染UCP3组脂肪氧化下降39.6%(P<0.05)、43.8%(P<0.01)；(3)感染UCP3组、CPTla组及共感染UCP3和CPTla组在施加胰岛素后比GFP组2-脱氧葡萄糖摄取速率增加25.8%(P<0.01)、13.3%(P<0.05)及21.8%(P<0.05)；(4)感染UCP3组、CPTla组及共感染UCP3和CPTla组比感染GFP组活性氧生成增加39.3%(P<0.01),54.1%(P<0.001)及53.7%(P<0.001)；(5)与0.75mM辛酸相比,0.75mM油酸组UCP3 mRNA增加117.9%(P<0.001)；(6)与丙氨酸相比,WY14643、亮氨酸以及亮氨酸和WY14643共同干预组,UCP3 mRNA表达分别增加63.2%(P<0.001)、41.0%(P<0.01)以及66.7%(P<0.001)。(7)AICAR干预2小时后,UCP3 mRNA表达水平增加(P<0.001)。
结论：超表达UCP3能增加脂肪酸氧化水平和胰岛素敏感性,但没有减少活性氧产生；CPT1具有协同促进UCP3增加脂肪酸氧化水平的作用；长链脂肪酸能增加UCP3表达但中链脂肪酸对其没有影响；WY14643、亮氨酸和短时间AICAR干预能增加UCP3表达。
Purpose:To study the effect of overexpression of UCP3 in C2C12 myotubes on fatty acid oxidation and the production of reactive oxygen species, especially under the condition of co-overexpression of CPT1. And to study the effect of fatty acids, WY14643, leucine and AICAR on the expression of UCP3.
Methods:(1) To examine oleic acid oxidation rate and 2-deoxyglucose uptake rate by isotope method and to examine the production of superoxide by DHE fluorescence probe in C2C12 myotubes which were infected with UCP3 recombinant adenovirus and CPTla recombinant adenovirus which were prepared by cloning technique. (2) To examine the expression of UCP3 mRNA by real time RT-PCR in in C2C12 myotubes which are treated with fatty acids, WY14643, leucine and AICAR.
Results:(1) Fatty acid oxidation was significantly increased by 62.8%(P< 0.01),80.2%(P< 0.001) respectively after infected with Adv-UCP3, Adv-CPTla, and increased by 168.4%(P<0.001) when co-infected cells with Adv-UCP3 and Adv-CPTla compared with corresponding Adv-GFP-infected myotubes. And more interestingly, fatty acid oxidation was markedly increased by 64.8%(P<0.001),48.9%(P<0.001),63.0%(P <0.001) when co-infected with Adv-UCP3 and Adv-CPTla compared with Adv-UCP3, Adv-CPTla, co-Adv-UCP3-Adv-GFP infected myotubes respectively. (2) Furthermore, fatty acid oxidation was reduced by 39.6%(P<0.05) and 43.8%(P<0.01) respectively in the absence of carnitine (activator of CPT1) and in the presence of etomoxir (inhibitor of CPT1) even upregulated expression of UCP3. (3) 2-deoxyglucose uptake was significantly increased by 25.8%(P<0.01),13.3%(P<0.05) and 21.8% (P<0.05) respectively after infected with Adv-UCP3, Adv-CPTla, and co-infected with Adv-UCP3 and Adv-CPTla compared with corresponding Adv-GFP infected myotubes under the treatment of insulin. (4) On the other hand, over-expression of UCP3 and CPTla in C2C12 myotubes also increased the production of reactive oxygen species by 39.3%(P<0.01),54.1%(P < 0.001)after infected with Adv-UCP3, Adv-CPTla, and increased by 53.7%(P<0.001) when co-infected Adv-UCP3 with Adv-CPTla. (5) UCP3 mRNA and CPT1a mRNA were increased by 117.9% (P<0.001) and 117.2%(P<0.001) respectively compared with the treatment of 0.75mM caprylic acid. (6) Compared with the treatment of alanine, UCP3 mRNA was increased by 63.2%(P <0.001),41.0%(P<0.01) and 66.7%(P<0.001) and fatty acid oxidation was increased by 23.2%(P<0.01),21.2%(P<0.001) and 35.7%(P<0.001) under the treatment of WY14643 (agonist of PPAR a), leucine and co-treatment of WY14643 and leucine respectively. (7) UCP3 mRNA and fatty acid oxidation were increased significantly (P<0.001) after 2 hours under the treatment of AICAR, but UCP3 mRNA was not changeable after 6 hours and 24 hours treatment of AICAR.
Conclusion:Overexpression of UCP3 may significantly increase fatty acid oxidation and insulin sensitivity, but don't decrease the production of reactive oxygen species. CPT1 promote the effect of UCP3 on increasing fatty acid oxidation.long-chain fatty acid but not medium-chain fatty acid increased the expression of UCP3. WY14643 and leucine increased the expression of UCP3 and the capacity of fatty acid oxidation while AICAR involve in this role at the early stage of its treatment.
引文
1. Ricquier, D. and F. Bouillaud, The uncoupling protein homologues:UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J,2000.345 Pt 2:p.161-79.
2. Adams, S.H., Uncoupling protein homologs:emerging views of physiological function. J Nutr,2000.130(4):p.711-4.
3. Harper, M.E., et al., UCP3 and its putative function:consistencies and controversies. Biochem Soc Trans,2001.29(Pt 6):p.768-73.
4. Hesselink, M.K., et al., Divergent effects of acute exercise and endurance training on UCP3 expression. Am J Physiol Endocrinol Metab,2003.284(2):p. E449-50; author reply 450-1.
5. Boss, O., et al., Uncoupling protein-3:a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett,1997.408(1):p.39-42.
6. Cannon, B. and J. Nedergaard, Brown adipose tissue:function and physiological significance. Physiol Rev,2004.84(1):p.277-359.
7. Walder, K., et al., Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians. Hum Mol Genet,1998.7(9):p.1431-5.
8. Clapham, J.C., et al., Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature,2000.406(6794):p.415-8.
9. Hinz, W., et al., Recombinant human uncoupling protein-3 increases thermogenesis in yeast cells. FEBS Lett,1999.448(1):p.57-61.
10. Zhang, C.Y., et al., Assessment of uncoupling activity of uncoupling protein 3 using a yeast heterologous expression system. FEBS Lett,1999.449(2-3):p.129-34.
11. Cadenas, S., et al., UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged. FEBS Lett,1999.462(3):p.257-60.
12. Samec, S., J. Seydoux, and A.G. Dulloo, Interorgan signaling between adipose tissue metabolism and skeletal muscle uncoupling protein homologs:is there a role for circulating free fatty acids? Diabetes,1998.47(11):p.1693-8.
13. Bezaire, V., et al., Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(-/-) and wild-type mice. Am J Physiol Endocrinol Metab,2001. 281(5):p. E975-82.
14. Gong, D.W., et al., Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J Biol Chem,2000.275(21):p.16251-7.
15. Vidal-Puig, A.J., et al., Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem,2000.275(21):p.16258-66.
16. Millet, L., et al., Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. J Clin Invest,1997.100(11):p.2665-70.
17. Weigle, D.S., et al., Elevated free fatty acids induce uncoupling protein 3 expression in muscle:a potential explanation for the effect of fasting. Diabetes,1998.47(2):p. 298-302.
18. Jimenez, M., et al., Expression of uncoupling protein-3 in subsarcolemmal and intermyofibrillar mitochondria of various mouse muscle types and its modulation by fasting. Eur J Biochem,2002.269(12):p.2878-84.
19. Tunstall, R.J., et al., Fasting activates the gene expression of UCP3 independent of genes necessary for lipid transport and oxidation in skeletal muscle. Biochem Biophys Res Commun,2002.294(2):p.301-8.
20. Matsuda, J., et al., Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their gene expression in rats fed high-fat diet. FEBS Lett,1997.418(1-2):p.200-4.
21. Surwit, R.S., et al., Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci U S A,1998.95(7):p.4061-5.
22. Samec, S., J. Seydoux, and A.G. Dulloo, Post-starvation gene expression of skeletal muscle uncoupling protein 2 and uncoupling protein 3 in response to dietary fat levels and fatty acid composition:a link with insulin resistance. Diabetes,1999.48(2):p. 436-41.
23. Gong, D.W., Y. He, and M.L. Reitman, Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes. Biochem Biophys Res Commun,1999. 256(1):p.27-32.
24. Brun, S., et al., Uncoupling protein-3 gene expression in skeletal muscle during development is regulated by nutritional factors that alter circulating non-esterified fatty acids. FEBS Lett,1999.453(1-2):p.205-9.
25. Schrauwen, P., et al., Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet. Int J Obes Relat Metab Disord,2001.25(4): p.449-56.
26. Schrauwen, P., et al., Uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB J,2003.17(15):p.2272-4.
27. Arkinstall, M.J., et al., Regulation of metabolic genes in human skeletal muscle by short-term exercise and diet manipulation. Am J Physiol Endocrinol Metab,2004.287(1): p. E25-31.
28. Tsuboyama-Kasaoka, N., et al., Up-regulation of uncoupling protein 3 (UCP3) mRNA by exercise training and down-regulation of UCP3 by denervation in skeletal muscles. Biochem Biophys Res Commun,1998.247(2):p.498-503.
29. Cortright, R.N., et al., Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation. Am J Physiol,1999.276(1 Pt 1):p. E217-21.
30. Pilegaard, H., et al., Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. Am J Physiol Endocrinol Metab,2000.279(4):p. E806-14.
31. Zhou, M., et al., UCP-3 expression in skeletal muscle:effects of exercise, hypoxia, and AMP-activated protein kinase. Am J Physiol Endocrinol Metab,2000.279(3):p. E622-9.
32. Schrauwen, P., et al., Effect of acute exercise on uncoupling protein 3 is a fat metabolism-mediated effect. Am J Physiol Endocrinol Metab,2002.282(1):p. E11-7.
33. Noland, R.C., et al., Acute endurance exercise increases skeletal muscle uncoupling protein-3 gene expression in untrained but not trained humans. Metabolism,2003.52(2): p.152-8.
34. MacLellan, J.D., et al., Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes,2005.54(8):p.2343-50.
35. Bezaire, V., et al., Constitutive UCP3 overexpression at physiological levels increases mouse skeletal muscle capacity for fatty acid transport and oxidation. FASEB J,2005. 19(8):p.977-9.
36. Garcia-Martinez, C., et al., Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid vs. glucose oxidation. FASEB J,2001.15(11):p.2033-5.
37. Wang, S., et al., Increased fatty acid oxidation in transgenic mice overexpressing UCP3 in skeletal muscle. Diabetes Obes Metab,2003.5(5):p.295-301.
38. Hesselink, M.K., et al., Protein expression of UCP3 differs between human type 1, type 2a, and type 2b fibers. FASEB J,2001.15(6):p.1071-3.
39. Hoeks, J., et al., Differential response of UCP3 to medium versus long chain triacylglycerols; manifestation of a functional adaptation. FEBS Lett,2003.555(3):p. 631-7.
40. Russell, A.P., et al., UCP3 protein expression is lower in type Ⅰ, Ⅱa and Ⅱx muscle fiber types of endurance-trained compared to untrained subjects. Pflugers Arch,2003.445(5): p.563-9.
41. Schrauwen, P., et al., Effect of 2 weeks of endurance training on uncoupling protein 3 content in untrained human subjects. Acta Physiol Scand,2005.183(3):p.273-80.
42. Vidal-Puig, A., et al., Effects of obesity and stable weight reduction on UCP2 and UCP3 gene expression in humans. Obes Res,1999.7(2):p.133-40.
43. Schrauwen, P., et al., The effect of weight reduction on skeletal muscle UCP2 and UCP3 mRNA expression and UCP3 protein content in Type Ⅱ diabetic subjects. Diabetologia, 2000.43(11):p.1408-16.
44. Mingrone, G., et al., Decreased uncoupling protein expression and intramyocytic triglyceride depletion in formerly obese subjects. Obes Res,2003.11(5):p.632-40.
45. Samec, S., J. Seydoux, and A.G. Dulloo, Skeletal muscle UCP3 and UCP2 gene expression in response to inhibition of free fatty acid flux through mitochondrial beta-oxidation. Pflugers Arch,1999.438(4):p.452-7.
46. Schrauwen, P., et al., Etomoxir-induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB J,2002.16(12):p. 1688-90.
47. Cabrero, A., et al., Uncoupling protein-3 mRNA up-regulation in C2C12 myotubes after etomoxir treatment. Biochim Biophys Acta,2001.1532(3):p.195-202.
48. Cabrero, A., et al., Etomoxir, sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, up-regulates uncoupling protein-3 mRNA levels in primary culture of rat preadipocytes. Biochem Biophys Res Commun,1999.263(1):p.87-93.
49. Friedman M. I., I.R., C. R. Bowden, and M. G.Tordoff, Fuel partitioning and food intake: role for mitochondrial fatty acid transport. Am J Physiol Regulatory Integrative Comp Physiol,1990.258:p. R216-R212.
50. Fujino, T., et al., Molecular identification and characterization of two medium-chain acyl-CoA synthetases, MACSI and the Sa gene product. J Biol Chem,2001.276(38):p. 35961-6.
51. Echtay, K.S., et al., Superoxide activates mitochondrial uncoupling proteins. Nature, 2002.415(6867):p.96-9.
52. Echtay, K.S., et al., A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J,2003.22(16):p.4103-10.
53. Duval, C., et al., Overexpression of mitochondrial uncoupling protein-3 does not decrease production of the reactive oxygen species, elevated by palmitate in skeletal muscle cells. FEBS Lett,2007.581(5):p.955-61.
54. Patel, B.P., et al., Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS. PLoS One,2010.5(2):p. e9386.
55. McGarry, J.D., et al., Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem J,1983.214(1):p.21-8.
56. Britton, C.H., et al., Human liver mitochondrial carnitine palmitoyltransferase Ⅰ: characterization of its cDNA and chromosomal localization and partial analysis of the gene. Proc Natl Acad Sci U S A,1995.92(6):p.1984-8.
57. Yamazaki, N., et al., Isolation and characterization of cDNA and genomic clones encoding human muscle type carnitine palmitoyltransferase Ⅰ. Biochim Biophys Acta, 1996.1307(2):p.157-61.
58. Price, N., et al., A novel brain-expressed protein related to carnitine palmitoyltransferase Ⅰ. Genomics,2002.80(4):p.433-42.
59. Perdomo, G, et al., Increased beta-oxidation in muscle cells enhances insulin-stimulated glucose metabolism and protects against fatty acid-induced insulin resistance despite intramyocellular lipid accumulation. J Biol Chem,2004.279(26):p.27177-86.
60. Bruce, C.R., et al., Overexpression of carnitine palmitoyltransferase I in skeletal muscle in vivo increases fatty acid oxidation and reduces triacylglycerol esterification. Am J Physiol Endocrinol Metab,2007.292(4):p. E1231-7.
61. Bruce, C.R., et al., Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes,2009.58(3):p.550-8.
62. Senese, R., et al., Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways. Pflugers Arch,2010.
63. Cooney, G.J., et al., Muscle long-chain acyl CoA esters and insulin resistance. Ann N Y Acad Sci,2002.967:p.196-207.
64. Pan, D.A., et al., Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes,1997.46(6):p.983-8.
65. Schrauwen, P., et al., Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes,2001.50(12):p.2870-3.
66. Choi, C.S., et al., Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. J Clin Invest,2007.117(7):p.1995-2003.
67. Costford, S.R., et al., Effects of the presence, absence, and overexpression of uncoupling protein-3 on adiposity and fuel metabolism in congenic mice. Am J Physiol Endocrinol Metab,2006.290(6):p. E1304-12.
68. Costford, S.R., et al., Long-term high-fat feeding induces greater fat storage in mice lacking UCP3. Am J Physiol Endocrinol Metab,2008.295(5):p. E1018-24.
69. Acin, A., et al., Cloning and characterization of the 5'flanking region of the human uncoupling protein 3 (UCP3) gene. Biochem Biophys Res Commun,1999.258(2):p. 278-83.
70. Murray, A.J., et al., Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels. Diabetes,2005. 54(12):p.3496-502.
71. Anthony, J.C., et al., Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr,2001.131(3):p.856S-860S.
72. Nakai, N., et al., Effects of peroxisome proliferator-activated receptor alpha (PPARalpha) agonists on leucine-induced phosphorylation of translational targets in C2C12 cells. Biochim Biophys Acta,2008.1780(10):p.1101-5.
73. Sun, X. and M.B. Zemel, Leucine and calcium regulate fat metabolism and energy partitioning in murine adipocytes and muscle cells. Lipids,2007.42(4):p.297-305.
74. Zhang, Y., et al., Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes, 2007.56(6):p.1647-54.
75. Borecky, J., I.G. Maia, and P. Arruda, Mitochondrial uncoupling proteins in mammals andplants. Biosci Rep,2001.21(2):p.201-12.
76. Klingenberg, M. and S.G. Huang, Structure and function of the uncoupling protein from brown adipose tissue. Biochim Biophys Acta,1999.1415(2):p.271-96.
77. Nicholls, D.G. and R.M. Locke, Thermogenic mechanisms in brown fat. Physiol Rev, 1984.64(1):p.1-64.
78. Nicholls, D.G. and E. Rial, A history of the first uncoupling protein, UCPI. J Bioenerg Biomembr,1999.31(5):p.399-406.
79. Fleury, C., et al., Uncoupling protein-2:a novel gene linked to obesity and hyperinsulinemia. Nat Genet,1997.15(3):p.269-72.
80. Gimeno, R.E., et al., Cloning and characterization of an uncoupling protein homolog:a potential molecular mediator of human thermogenesis. Diabetes,1997.46(5):p.900-6.
81. Solanes, G., et al., The human uncoupling protein-3 gene. Genomic structure, chromosomal localization, and genetic basis for short and long form transcripts. J Biol Chem,1997.272(41):p.25433-6.
82. Gong, D.W., et al., Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem,1997.272(39):p. 24129-32.
83. Esterbauer, H., et al., The uncoupling protein-3 gene is transcribed from tissue-specific promoters in humans but not in rodents. J Biol Chem,2000.275(46):p.36394-9.
84. Vidal-Puig, A., et al., UCP3:an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun,1997.235(1):p.79-82.
85. Harper, J.A., et al., Artifactual uncoupling by uncoupling protein 3 in yeast mitochondria at the concentrations found in mouse and rat skeletal-muscle mitochondria. Biochem J, 2002.361(Pt 1):p.49-56.
86. Mitchell, P., Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Biol Rev Camb Philos Soc,1966.41(3):p.445-502.
87. Brand, M.D., The contribution of the leak of protons across the mitochondrial inner membrane to standard metabolic rate. J Theor Biol,1990.145(2):p.267-86.
88. Rolfe, D.F. and G.C. Brown, Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev,1997.77(3):p.731-58.
89. Heaton, G.M., et al., Brown-adipose-tissue mitochondria:photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem,1978.82(2):p.515-21.
90. Enerback, S., et al., Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature,1997.387(6628):p.90-4.
91. Schrauwen, P., et al., Skeletal muscle uncoupling protein 3 expression is a determinant of energy expenditure in Pima Indians. Diabetes,1999.48(1):p.146-9.
92. Lanouette, C.M., et al., Association between uncoupling protein 3 gene and obesity-related phenotypes in the Quebec Family Study. Mol Med,2001.7(7):p.433-41.
93. Matsuda, J., et al., Increased adipose expression of the uncoupling protein-3 gene by thiazolidinediones in Wistar fatty rats and in cultured adipocytes. Diabetes,1998.47(11): p.1809-14.
94. Emilsson, V., et al., The effects of the beta3-adrenoceptor agonist BRL 35135 on UCP isoform mRNA expression. Biochem Biophys Res Commun,1998.252(2):p.450-4.
95. Tiraby, C, et al., Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles. Diabetologia,2007.50(10):p.2190-9.
96. Guerini, D., et al., Uncoupling of protein-3 induces an uncontrolled uncoupling of mitochondria after expression in muscle derived L6 cells. Eur J Biochem,2002.269(5):p. 1373-81.
97. Cadenas, S., et al., The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3. J Biol Chem,2002. 277(4):p.2773-8.
98. Bevilacqua, L., et al., Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab,2005.289(3):p. E429-38.
99. Brand, M.D. and T.C. Esteves, Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab,2005.2(2):p.85-93.
100. Chance, B., H. Sies, and A. Boveris, Hydroperoxide metabolism in mammalian organs. Physiol Rev,1979.59(3):p.527-605.
101. Korshunov, S.S., V.P. Skulachev, and A.A. Starkov, High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett,1997. 416(1):p.15-8.
102. Papa, S. and V.P. Skulachev, Reactive oxygen species, mitochondria, apoptosis and aging. Mol Cell Biochem,1997.174(1-2):p.305-19.
103. Brand, M.D., et al., The significance and mechanism of mitochondrial proton conductance. Int J Obes Relat Metab Disord,1999.23 Suppl 6:p. S4-11.
104. Flandin, P., et al., Hyperoxia-mediated oxidative stress increases expression of UCP3 mRNA and protein in skeletal muscle. FEBS Lett,2005.579(16):p.3411-5.
105. Brand, M.D., et al., Oxidative damage andphospholipidfatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3. Biochem J,2002.368(Pt 2):p.597-603.
106. Anderson, E.J., H. Yamazaki, and P.D. Neufer, Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration. J Biol Chem,2007.282(43):p.31257-66.
107. Jiang, N., et al., Upregulation of uncoupling protein-3 in skeletal muscle during exercise: a potential antioxidant function. Free Radic Biol Med,2009.46(2):p.138-45.
108. Mozo, J., et al., Expression of UCP3 in CHO cells does not cause uncoupling, but controls mitochondrial activity in the presence of glucose. Biochem J,2006.393(Pt 1):p. 431-9.
109. Gerber, L.K., B.J. Aronow, and M.A. Matlib, Activation of a novel long-chain free fatty acid generation and export system in mitochondria of diabetic rat hearts. Am J Physiol Cell Physiol,2006.291(6):p. C1198-207.
110. Himms-Hagen, J. and M.E. Harper, Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates:an hypothesis. Exp Biol Med (Maywood),2001.226(2):p.78-84.
111. Moore, G.B., et al., Overexpression of UCP-3 in skeletal muscle of mice results in increased expression of mitochondrial thioesterase mRNA. Biochem Biophys Res Commun,2001.283(4):p.785-90.
112. Moreno, M., et al., Fasting, lipid metabolism, and triiodothyronine in rat gastrocnemius muscle:interrelated roles of uncoupling protein 3, mitochondrial thioesterase, and coenzyme Q. FASEB J,2003.17(9):p.1112-4.
113. McGarry, J.D. and N.F. Brown, The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem,1997.244(1):p.1-14.
114. Kerner, J. and C. Hoppel, Fatty acid import into mitochondria. Biochim Biophys Acta, 2000.1486(1):p.1-17.
115. Declercq, P.E., et al., Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. I. Use of inhibitors. J Biol Chem,1987.262(20):p. 9812-21.
116. Cabrero, A., et al., Increased reactive oxygen species production down-regulates peroxisome proliferator-activated alpha pathway in C2C12 skeletal muscle cells. J Biol Chem,2002.277(12):p.10100-7.
117. Schrauwen, P., W.H. Saris, and M.K. Hesselink, An alternative function for human uncoupling protein 3:protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix. FASEB J,2001.15(13):p.2497-502.
118. Schrauwen, P. and M.K. Hesselink, The role of uncoupling protein 3 in fatty acid metabolism:protection against lipotoxicity? Proc Nutr Soc,2004.63(2):p.287-92.
119. Hamilton, J.A. and F. Kamp, How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? Diabetes,1999.48(12):p.2255-69.
120. Seifert, E.L., et al., Essential role for uncoupling protein-3 in mitochondrial adaptation to fasting but not in fatty acid oxidation or fatty acid anion export. J Biol Chem,2008. 283(37):p.25124-31.
121. Adams, J.M.,2nd, et al., Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes,2004.53(1):p.25-31.
122. Itani, S.I., et al., Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes,2002.51(7):p. 2005-11.
123. Li, Y., et al., UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells. PLoS One,2008.3(1):p. e1397.
124. Schrauwen, P., et al., Reduced skeletal muscle uncoupling protein-3 content in prediabetic subjects and type 2 diabetic patients:restoration by rosiglitazone treatment. J Clin Endocrinol Metab,2006.91(4):p.1520-5.
125. Huppertz, C., et al., Uncoupling protein 3 (UCP3) stimulates glucose uptake in muscle cells through a phosphoinositide 3-kinase-dependent mechanism. J Biol Chem,2001. 276(16):p.12520-9.
126. Pedersen, S.B., et al., Regulation of uncoupling protein (UCP) 2 and 3 in adipose and muscle tissue by fasting and growth hormone treatment in obese humans. Int J Obes Relat Metab Disord,2000.24(8):p.968-75.
127. Esterbauer, H., et al., Uncoupling protein-3 gene expression:reduced skeletal muscle mRNA in obese humans during pronounced weight loss. Diabetologia,1999.42(3):p. 302-9.
128. Hwang, C.S. and M.D. Lane, Up-regulation of uncoupling protein-3 by fatty acid in C2C12 myotubes. Biochem Biophys Res Commun,1999.258(2):p.464-9.
129. Sbraccia, P., et al., Relationship between plasma free fatty acids and uncoupling protein-3 gene expression in skeletal muscle of obese subjects:in vitro evidence of a causal link. Clin Endocrinol (Oxf),2002.57(2):p.199-207.
130. Cabrero, A., et al., Down-regulation of uncoupling protein-3 and-2 by thiazolidinediones in C2C12 myotubes. FEBS Lett,2000.484(1):p.37-42.
131. Costello, A., S. Gray, and R. Donnelly, Effects of rosiglitazone and oleic acid on UCP-3 expression in L6 myotubes. Diabetes Obes Metab,2003.5(2):p.136-8.
132. Nagase, I., et al., Up-regulation of uncoupling protein 3 by thyroid hormone, peroxisome proliferator-activated receptor ligands and 9-cis retinoic acid in L6 myotubes. FEBS Lett, 1999.461(3):p.319-22.
133. Son, C., et al., Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes. Endocrinology,2001.142(10):p.4189-94.
134. Jones, T.E., et al., Exercise induces an increase in muscle UCP3 as a component of the increase in mitochondrial biogenesis. Am J Physiol Endocrinol Metab,2003.284(1):p. E96-101.
135. Boss, O., et al., Effect of endurance training on mRNA expression of uncoupling proteins 1,2, and 3 in the rat. FASEB J,1998.12(3):p.335-9.
136. Fernstrom, M., M. Tonkonogi, and K. Sahlin, Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle. J Physiol,2004.554(Pt 3):p.755-63.
137. Schrauwen, P., et al., Skeletal muscle UCP2 and UCP3 expression in trained and untrained male subjects. Int J Obes Relat Metab Disord,1999.23(9):p.966-72.
138. Kliewer, S.A., et al., Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A,1994.91(15):p. 7355-9.
139. Qi, C., Y. Zhu, and J.K. Reddy, Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys,2000.32 Spring:p.187-204.
140. Abbott, B.D., Review of the expression of peroxisome proliferator-activated receptors alpha (PPAR alpha), beta (PPAR beta), and gamma (PPAR gamma) in rodent and human development. Reprod Toxicol,2009.27(3-4):p.246-57.
141. Feige, J.N., et al., Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand. J Biol Chem,2005.280(18):p.17880-90.
142. Forman, B.M., J. Chen, and R.M. Evans, Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A,1997.94(9):p.4312-7.
143. Gervois, P., J.C. Fruchart, and B. Staels, Drug Insight:mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab,2007.3(2):p.145-56.
144. Tu, N., et al., Molecular cloning and functional characterization of the promoter region of the human uncoupling protein-2 gene. Biochem Biophys Res Commun,1999.265(2): p.326-34.
145. Solanes, G., et al., Functional relationship between MyoD and peroxisome proliferator-activated receptor-dependent regulatory pathways in the control of the human uncoupling protein-3 gene transcription. Mol Endocrinol,2003.17(10):p. 1944-58.
146. Pedraza, N., et al., Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation:fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. Diabetes,2000.49(7):p.1224-30.
147. Young, M.E., et al., Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J,2001.15(3):p. 833-45.
148. Cabrero, A., et al., Peroxisome proliferator-activated receptor alpha (PPARalpha) activators, bezafibrate and Wy-14,643, increase uncoupling protein-3 mRNA levels without modifying the mitochondrial membrane potential in primary culture of rat preadipocytes. Arch Biochem Biophys,2000.380(2):p.353-9.
149. Hardie, D.G, S.A. Hawley, and J.W. Scott, AMP-activated protein kinase--development of the energy sensor concept. J Physiol,2006.574(Pt 1):p.7-15.
150. Steinberg, G.R. and B.E. Kemp, AMPK in Health and Disease. Physiol Rev,2009.89(3): p.1025-78.
151. Zheng, D., et al., Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol,2001.91(3):p.1073-83.
152. Stoppani, J., et al., AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle. Am J Physiol Endocrinol Metab,2002.283(6):p. E1239-48.
153. Chabowski, A., et al., Prolonged AMPK activation increases the expression of fatty acid transporters in cardiac myocytes and perfused hearts. Mol Cell Biochem,2006.288(1-2): p.201-12.
154. Barnes, B.R., et al., Changes in exercise-induced gene expression in 5'-AMP-activated protein kinase gammai-null and gamma3 R225Q transgenic mice. Diabetes,2005. 54(12):p.3484-9.
155. Corton, J.M., et al.,5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem,1995.229(2): p.558-65.
156. Pedersen, S.B., et al., Insulin and contraction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal muscle in vitro. Biochem Biophys Res Commun,2001.283(1): p.19-25.
157. Putman, C.T., et al., AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions. J Physiol, 2003.551(Pt 1):p.169-78.
158. Suwa, M., H. Nakano, and S. Kumagai, Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J Appl Physiol,2003. 95(3):p.960-8.
159. Li, J.B. and L.S. Jefferson, Influence of amino acid availability on protein turnover in perfused skeletal muscle. Biochim Biophys Acta,1978.544(2):p.351-9.
160. Hong, S.O. and D.K. Layman, Effects of leucine on in vitro protein synthesis and degradation in rat skeletal muscles. J Nutr,1984.114(7):p.1204-12.
161. Anthony, J.C., et al., Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J Nutr, 2000.130(2):p.139-45.
162. Anthony, J.C., et al., Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. Diabetes,2002.51(4):p.928-36.
163. Crozier, S.J., et al., Oral leucine administration stimulates protein synthesis in rat skeletal muscle. J Nutr,2005.135(3):p.376-82.
164. Kimball, S.R., et al., Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem,1999.274(17):p.11647-52.
165. Sun, X. and M.B. Zemel, Leucine modulation of mitochondrial mass and oxygen consumption in skeletal muscle cells and adipocytes. Nutr Metab (Lond),2009.6:p.26.
166. Volpers, C. and S. Kochanek, Adenoviral vectors for gene transfer and therapy. J Gene Med,2004.6 Suppl 1:p. S164-71.
167. Danthinne, X. and M.J. Imperiale, Production of first generation adenovirus vectors:a review. Gene Ther,2000.7(20):p.1707-14.
168. Engelhardt, J.F., et al., Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc Natl Acad Sci U S A,1994.91(13):p.6196-200.
169. Armentano, D., et al., Characterization of an adenovirus gene transfer vector containing an E4 deletion. Hum Gene Ther,1995.6(10):p.1343-53.
170. Yang, Y., et al., Cellular immunity to viral antigens limits EI-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A,1994.91(10):p.4407-11.
171. Mitani, K., et al., Rescue, propagation, and partial purification of a helper virus-dependent adenovirus vector. Proc Natl Acad Sci U S A,1995.92(9):p.3854-8.
172. Kochanek, S., G. Schiedner, and C. Volpers, High-capacity'gutless'adenoviral vectors. Curr Opin Mol Ther,2001.3(5):p.454-63.
173. Morsy, M.A., et al., An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc Natl Acad Sci U S A, 1998.95(14):p.7866-71.
174. Schiedner, G., et al., Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet,1998. 18(2):p.180-3.
175. Luo, J., et al., A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc,2007.2(5):p.1236-47.
176. Mao, X., et al., APPLI binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol,2006.8(5):p.516-23.
177. Chomczynski, P. and N. Sacchi, Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem,1987.162(1):p. 156-9.
178. Negre-Salvayre, A., et al., Detection of intracellular reactive oxygen species in cultured cells using fluorescent probes. Methods Enzymol,2002.352:p.62-71.
179. Tsakiridis, T., M. Vranic, and A. Klip, Disassembly of the actin network inhibits insulin-dependent stimulation of glucose transport and prevents recruitment of glucose transporters to the plasma membrane. J Biol Chem,1994.269(47):p.29934-42.
180. Bieber, L.L., T. Abraham, and T. Helmrath, A rapid spectrophotometric assay for carnitine palmitoyltransferase. Anal Biochem,1972.50(2):p.509-18.
181. Rubi, B., et al., Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase Ⅰ in INS1E cells:effects on cell metabolism and insulin secretion. Biochem J,2002.364(Pt 1):p.219-26.
182. Shimokawa, T., et al., Transcriptional regulation of muscle-specific genes during myoblast differentiation. Biochem Biophys Res Commun,1998.246(1):p.287-92.
183. Eaton, S., Control of mitochondrial beta-oxidation flux. Prog Lipid Res,2002.41(3):p. 197-239.
184. Svensson, L.T., et al., Molecular cloning and characterization of a mitochondrial peroxisome proliferator-induced acyl-CoA thioesterase from rat liver. Biochem J,1998. 329 (Pt 3):p.601-8.
185. Brass, E.P., Pharmacokinetic considerations for the therapeutic use of carnitine in hemodialysis patients. Clin Ther,1995.17(2):p.176-85; discussion 175.
186. Brooks, D.E. and J.E. McIntosh, Turnover of carnitine by rat tissues. Biochem J,1975. 148(3):p.439-45.
187. Cederblad, G., S. Lindstedt, and K. Lundholm, Concentration of carnitine in human muscle tissue. Clin Chim Acta,1974.53(3):p.311-21.
188. Engel, A.G. and C. Angelini, Carnitine deficiency of human skeletal muscle with associated lipidstorage myopathy:a new syndrome. Science,1973.179(76):p.899-902.
189. Stephens, F.B., et al., An acute increase in skeletal muscle carnitine content alters fuel metabolism in resting human skeletal muscle. J Clin Endocrinol Metab,2006.91(12):p. 5013-8.
190. Skulachev, V.P., Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett,1991.294(3):p.158-62.
191. Garlid, K.D., M. Jaburek, and P. Jezek, The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett,1998.438(1-2):p.10-4.
192. Jezek, P., et al., Transport of anions and protons by the mitochondrial uncoupling protein and its regulation by nucleotides and fatty acids. A new look at old hypotheses. J Biol Chem,1994.269(42):p.26184-90.
193. Severin, F.F., et al., Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc Natl Acad Sci U S A,2010.107(2):p.663-8.
194. Adams, S.H., et al., Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr,2009.139(6):p.1073-81.
195. Sebastian, D., et al., CPT I overexpression protects L6E9 muscle cells from fatty acid-induced insulin resistance. Am J Physiol Endocrinol Metab,2007.292(3):p. E677-86.
196. Randle, P.J., et al., The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet,1963.1(7285):p.785-9.
197. Bouzakri, K., et al., Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle. Diabetes,2008.57(6):p.1508-16.
198. Koves, T.R., et al., Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab,2008.7(1):p.45-56.
199. Shulman, G.I., Cellular mechanisms of insulin resistance. J Clin Invest,2000.106(2):p. 171-6.
200. Roden, M., et al., Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest,1996.97(12):p.2859-65.
201. Gilde, A.J. and M. Van Bilsen, Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand,2003. 178(4):p.425-34.
202. Aoyama, T., et al., Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem,1998.273(10):p.5678-84.
203. Leone, T.C., C.J. Weinheimer, and D.P. Kelly, A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response:the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A,1999.96(13):p.7473-8.
204. Brun, S., et al., Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle:a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. Diabetes,1999.48(6):p.1217-22.
205. Winder, W.W., et al., Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol,2000.88(6):p.2219-26.
206. Merrill, G.F., et al., AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol,1997.273(6 Pt 1):p. E1107-12.
207. Ruderman, N.B., et al., Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol, 1999.276(1 Pt 1):p. E1-E18.
2. Adams, S.H., Uncoupling protein homologs:emerging views of physiological function. J Nutr,2000.130(4):p.711-4.
3. Harper, M.E., et al., UCP3 and its putative function:consistencies and controversies. Biochem Soc Trans,2001.29(Pt 6):p.768-73.
4. Hesselink, M.K., et al., Divergent effects of acute exercise and endurance training on UCP3 expression. Am J Physiol Endocrinol Metab,2003.284(2):p. E449-50; author reply 450-1.
5. Boss, O., et al., Uncoupling protein-3:a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett,1997.408(1):p.39-42.
6. Cannon, B. and J. Nedergaard, Brown adipose tissue:function and physiological significance. Physiol Rev,2004.84(1):p.277-359.
7. Walder, K., et al., Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians. Hum Mol Genet,1998.7(9):p.1431-5.
8. Clapham, J.C., et al., Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature,2000.406(6794):p.415-8.
9. Hinz, W., et al., Recombinant human uncoupling protein-3 increases thermogenesis in yeast cells. FEBS Lett,1999.448(1):p.57-61.
10. Zhang, C.Y., et al., Assessment of uncoupling activity of uncoupling protein 3 using a yeast heterologous expression system. FEBS Lett,1999.449(2-3):p.129-34.
11. Cadenas, S., et al., UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged. FEBS Lett,1999.462(3):p.257-60.
12. Samec, S., J. Seydoux, and A.G. Dulloo, Interorgan signaling between adipose tissue metabolism and skeletal muscle uncoupling protein homologs:is there a role for circulating free fatty acids? Diabetes,1998.47(11):p.1693-8.
13. Bezaire, V., et al., Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(-/-) and wild-type mice. Am J Physiol Endocrinol Metab,2001. 281(5):p. E975-82.
14. Gong, D.W., et al., Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J Biol Chem,2000.275(21):p.16251-7.
15. Vidal-Puig, A.J., et al., Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem,2000.275(21):p.16258-66.
16. Millet, L., et al., Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. J Clin Invest,1997.100(11):p.2665-70.
17. Weigle, D.S., et al., Elevated free fatty acids induce uncoupling protein 3 expression in muscle:a potential explanation for the effect of fasting. Diabetes,1998.47(2):p. 298-302.
18. Jimenez, M., et al., Expression of uncoupling protein-3 in subsarcolemmal and intermyofibrillar mitochondria of various mouse muscle types and its modulation by fasting. Eur J Biochem,2002.269(12):p.2878-84.
19. Tunstall, R.J., et al., Fasting activates the gene expression of UCP3 independent of genes necessary for lipid transport and oxidation in skeletal muscle. Biochem Biophys Res Commun,2002.294(2):p.301-8.
20. Matsuda, J., et al., Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their gene expression in rats fed high-fat diet. FEBS Lett,1997.418(1-2):p.200-4.
21. Surwit, R.S., et al., Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci U S A,1998.95(7):p.4061-5.
22. Samec, S., J. Seydoux, and A.G. Dulloo, Post-starvation gene expression of skeletal muscle uncoupling protein 2 and uncoupling protein 3 in response to dietary fat levels and fatty acid composition:a link with insulin resistance. Diabetes,1999.48(2):p. 436-41.
23. Gong, D.W., Y. He, and M.L. Reitman, Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes. Biochem Biophys Res Commun,1999. 256(1):p.27-32.
24. Brun, S., et al., Uncoupling protein-3 gene expression in skeletal muscle during development is regulated by nutritional factors that alter circulating non-esterified fatty acids. FEBS Lett,1999.453(1-2):p.205-9.
25. Schrauwen, P., et al., Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet. Int J Obes Relat Metab Disord,2001.25(4): p.449-56.
26. Schrauwen, P., et al., Uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB J,2003.17(15):p.2272-4.
27. Arkinstall, M.J., et al., Regulation of metabolic genes in human skeletal muscle by short-term exercise and diet manipulation. Am J Physiol Endocrinol Metab,2004.287(1): p. E25-31.
28. Tsuboyama-Kasaoka, N., et al., Up-regulation of uncoupling protein 3 (UCP3) mRNA by exercise training and down-regulation of UCP3 by denervation in skeletal muscles. Biochem Biophys Res Commun,1998.247(2):p.498-503.
29. Cortright, R.N., et al., Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation. Am J Physiol,1999.276(1 Pt 1):p. E217-21.
30. Pilegaard, H., et al., Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. Am J Physiol Endocrinol Metab,2000.279(4):p. E806-14.
31. Zhou, M., et al., UCP-3 expression in skeletal muscle:effects of exercise, hypoxia, and AMP-activated protein kinase. Am J Physiol Endocrinol Metab,2000.279(3):p. E622-9.
32. Schrauwen, P., et al., Effect of acute exercise on uncoupling protein 3 is a fat metabolism-mediated effect. Am J Physiol Endocrinol Metab,2002.282(1):p. E11-7.
33. Noland, R.C., et al., Acute endurance exercise increases skeletal muscle uncoupling protein-3 gene expression in untrained but not trained humans. Metabolism,2003.52(2): p.152-8.
34. MacLellan, J.D., et al., Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes,2005.54(8):p.2343-50.
35. Bezaire, V., et al., Constitutive UCP3 overexpression at physiological levels increases mouse skeletal muscle capacity for fatty acid transport and oxidation. FASEB J,2005. 19(8):p.977-9.
36. Garcia-Martinez, C., et al., Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid vs. glucose oxidation. FASEB J,2001.15(11):p.2033-5.
37. Wang, S., et al., Increased fatty acid oxidation in transgenic mice overexpressing UCP3 in skeletal muscle. Diabetes Obes Metab,2003.5(5):p.295-301.
38. Hesselink, M.K., et al., Protein expression of UCP3 differs between human type 1, type 2a, and type 2b fibers. FASEB J,2001.15(6):p.1071-3.
39. Hoeks, J., et al., Differential response of UCP3 to medium versus long chain triacylglycerols; manifestation of a functional adaptation. FEBS Lett,2003.555(3):p. 631-7.
40. Russell, A.P., et al., UCP3 protein expression is lower in type Ⅰ, Ⅱa and Ⅱx muscle fiber types of endurance-trained compared to untrained subjects. Pflugers Arch,2003.445(5): p.563-9.
41. Schrauwen, P., et al., Effect of 2 weeks of endurance training on uncoupling protein 3 content in untrained human subjects. Acta Physiol Scand,2005.183(3):p.273-80.
42. Vidal-Puig, A., et al., Effects of obesity and stable weight reduction on UCP2 and UCP3 gene expression in humans. Obes Res,1999.7(2):p.133-40.
43. Schrauwen, P., et al., The effect of weight reduction on skeletal muscle UCP2 and UCP3 mRNA expression and UCP3 protein content in Type Ⅱ diabetic subjects. Diabetologia, 2000.43(11):p.1408-16.
44. Mingrone, G., et al., Decreased uncoupling protein expression and intramyocytic triglyceride depletion in formerly obese subjects. Obes Res,2003.11(5):p.632-40.
45. Samec, S., J. Seydoux, and A.G. Dulloo, Skeletal muscle UCP3 and UCP2 gene expression in response to inhibition of free fatty acid flux through mitochondrial beta-oxidation. Pflugers Arch,1999.438(4):p.452-7.
46. Schrauwen, P., et al., Etomoxir-induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB J,2002.16(12):p. 1688-90.
47. Cabrero, A., et al., Uncoupling protein-3 mRNA up-regulation in C2C12 myotubes after etomoxir treatment. Biochim Biophys Acta,2001.1532(3):p.195-202.
48. Cabrero, A., et al., Etomoxir, sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, up-regulates uncoupling protein-3 mRNA levels in primary culture of rat preadipocytes. Biochem Biophys Res Commun,1999.263(1):p.87-93.
49. Friedman M. I., I.R., C. R. Bowden, and M. G.Tordoff, Fuel partitioning and food intake: role for mitochondrial fatty acid transport. Am J Physiol Regulatory Integrative Comp Physiol,1990.258:p. R216-R212.
50. Fujino, T., et al., Molecular identification and characterization of two medium-chain acyl-CoA synthetases, MACSI and the Sa gene product. J Biol Chem,2001.276(38):p. 35961-6.
51. Echtay, K.S., et al., Superoxide activates mitochondrial uncoupling proteins. Nature, 2002.415(6867):p.96-9.
52. Echtay, K.S., et al., A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J,2003.22(16):p.4103-10.
53. Duval, C., et al., Overexpression of mitochondrial uncoupling protein-3 does not decrease production of the reactive oxygen species, elevated by palmitate in skeletal muscle cells. FEBS Lett,2007.581(5):p.955-61.
54. Patel, B.P., et al., Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS. PLoS One,2010.5(2):p. e9386.
55. McGarry, J.D., et al., Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem J,1983.214(1):p.21-8.
56. Britton, C.H., et al., Human liver mitochondrial carnitine palmitoyltransferase Ⅰ: characterization of its cDNA and chromosomal localization and partial analysis of the gene. Proc Natl Acad Sci U S A,1995.92(6):p.1984-8.
57. Yamazaki, N., et al., Isolation and characterization of cDNA and genomic clones encoding human muscle type carnitine palmitoyltransferase Ⅰ. Biochim Biophys Acta, 1996.1307(2):p.157-61.
58. Price, N., et al., A novel brain-expressed protein related to carnitine palmitoyltransferase Ⅰ. Genomics,2002.80(4):p.433-42.
59. Perdomo, G, et al., Increased beta-oxidation in muscle cells enhances insulin-stimulated glucose metabolism and protects against fatty acid-induced insulin resistance despite intramyocellular lipid accumulation. J Biol Chem,2004.279(26):p.27177-86.
60. Bruce, C.R., et al., Overexpression of carnitine palmitoyltransferase I in skeletal muscle in vivo increases fatty acid oxidation and reduces triacylglycerol esterification. Am J Physiol Endocrinol Metab,2007.292(4):p. E1231-7.
61. Bruce, C.R., et al., Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes,2009.58(3):p.550-8.
62. Senese, R., et al., Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways. Pflugers Arch,2010.
63. Cooney, G.J., et al., Muscle long-chain acyl CoA esters and insulin resistance. Ann N Y Acad Sci,2002.967:p.196-207.
64. Pan, D.A., et al., Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes,1997.46(6):p.983-8.
65. Schrauwen, P., et al., Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes,2001.50(12):p.2870-3.
66. Choi, C.S., et al., Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. J Clin Invest,2007.117(7):p.1995-2003.
67. Costford, S.R., et al., Effects of the presence, absence, and overexpression of uncoupling protein-3 on adiposity and fuel metabolism in congenic mice. Am J Physiol Endocrinol Metab,2006.290(6):p. E1304-12.
68. Costford, S.R., et al., Long-term high-fat feeding induces greater fat storage in mice lacking UCP3. Am J Physiol Endocrinol Metab,2008.295(5):p. E1018-24.
69. Acin, A., et al., Cloning and characterization of the 5'flanking region of the human uncoupling protein 3 (UCP3) gene. Biochem Biophys Res Commun,1999.258(2):p. 278-83.
70. Murray, A.J., et al., Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels. Diabetes,2005. 54(12):p.3496-502.
71. Anthony, J.C., et al., Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr,2001.131(3):p.856S-860S.
72. Nakai, N., et al., Effects of peroxisome proliferator-activated receptor alpha (PPARalpha) agonists on leucine-induced phosphorylation of translational targets in C2C12 cells. Biochim Biophys Acta,2008.1780(10):p.1101-5.
73. Sun, X. and M.B. Zemel, Leucine and calcium regulate fat metabolism and energy partitioning in murine adipocytes and muscle cells. Lipids,2007.42(4):p.297-305.
74. Zhang, Y., et al., Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes, 2007.56(6):p.1647-54.
75. Borecky, J., I.G. Maia, and P. Arruda, Mitochondrial uncoupling proteins in mammals andplants. Biosci Rep,2001.21(2):p.201-12.
76. Klingenberg, M. and S.G. Huang, Structure and function of the uncoupling protein from brown adipose tissue. Biochim Biophys Acta,1999.1415(2):p.271-96.
77. Nicholls, D.G. and R.M. Locke, Thermogenic mechanisms in brown fat. Physiol Rev, 1984.64(1):p.1-64.
78. Nicholls, D.G. and E. Rial, A history of the first uncoupling protein, UCPI. J Bioenerg Biomembr,1999.31(5):p.399-406.
79. Fleury, C., et al., Uncoupling protein-2:a novel gene linked to obesity and hyperinsulinemia. Nat Genet,1997.15(3):p.269-72.
80. Gimeno, R.E., et al., Cloning and characterization of an uncoupling protein homolog:a potential molecular mediator of human thermogenesis. Diabetes,1997.46(5):p.900-6.
81. Solanes, G., et al., The human uncoupling protein-3 gene. Genomic structure, chromosomal localization, and genetic basis for short and long form transcripts. J Biol Chem,1997.272(41):p.25433-6.
82. Gong, D.W., et al., Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem,1997.272(39):p. 24129-32.
83. Esterbauer, H., et al., The uncoupling protein-3 gene is transcribed from tissue-specific promoters in humans but not in rodents. J Biol Chem,2000.275(46):p.36394-9.
84. Vidal-Puig, A., et al., UCP3:an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun,1997.235(1):p.79-82.
85. Harper, J.A., et al., Artifactual uncoupling by uncoupling protein 3 in yeast mitochondria at the concentrations found in mouse and rat skeletal-muscle mitochondria. Biochem J, 2002.361(Pt 1):p.49-56.
86. Mitchell, P., Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Biol Rev Camb Philos Soc,1966.41(3):p.445-502.
87. Brand, M.D., The contribution of the leak of protons across the mitochondrial inner membrane to standard metabolic rate. J Theor Biol,1990.145(2):p.267-86.
88. Rolfe, D.F. and G.C. Brown, Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev,1997.77(3):p.731-58.
89. Heaton, G.M., et al., Brown-adipose-tissue mitochondria:photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem,1978.82(2):p.515-21.
90. Enerback, S., et al., Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature,1997.387(6628):p.90-4.
91. Schrauwen, P., et al., Skeletal muscle uncoupling protein 3 expression is a determinant of energy expenditure in Pima Indians. Diabetes,1999.48(1):p.146-9.
92. Lanouette, C.M., et al., Association between uncoupling protein 3 gene and obesity-related phenotypes in the Quebec Family Study. Mol Med,2001.7(7):p.433-41.
93. Matsuda, J., et al., Increased adipose expression of the uncoupling protein-3 gene by thiazolidinediones in Wistar fatty rats and in cultured adipocytes. Diabetes,1998.47(11): p.1809-14.
94. Emilsson, V., et al., The effects of the beta3-adrenoceptor agonist BRL 35135 on UCP isoform mRNA expression. Biochem Biophys Res Commun,1998.252(2):p.450-4.
95. Tiraby, C, et al., Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles. Diabetologia,2007.50(10):p.2190-9.
96. Guerini, D., et al., Uncoupling of protein-3 induces an uncontrolled uncoupling of mitochondria after expression in muscle derived L6 cells. Eur J Biochem,2002.269(5):p. 1373-81.
97. Cadenas, S., et al., The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3. J Biol Chem,2002. 277(4):p.2773-8.
98. Bevilacqua, L., et al., Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab,2005.289(3):p. E429-38.
99. Brand, M.D. and T.C. Esteves, Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab,2005.2(2):p.85-93.
100. Chance, B., H. Sies, and A. Boveris, Hydroperoxide metabolism in mammalian organs. Physiol Rev,1979.59(3):p.527-605.
101. Korshunov, S.S., V.P. Skulachev, and A.A. Starkov, High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett,1997. 416(1):p.15-8.
102. Papa, S. and V.P. Skulachev, Reactive oxygen species, mitochondria, apoptosis and aging. Mol Cell Biochem,1997.174(1-2):p.305-19.
103. Brand, M.D., et al., The significance and mechanism of mitochondrial proton conductance. Int J Obes Relat Metab Disord,1999.23 Suppl 6:p. S4-11.
104. Flandin, P., et al., Hyperoxia-mediated oxidative stress increases expression of UCP3 mRNA and protein in skeletal muscle. FEBS Lett,2005.579(16):p.3411-5.
105. Brand, M.D., et al., Oxidative damage andphospholipidfatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3. Biochem J,2002.368(Pt 2):p.597-603.
106. Anderson, E.J., H. Yamazaki, and P.D. Neufer, Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration. J Biol Chem,2007.282(43):p.31257-66.
107. Jiang, N., et al., Upregulation of uncoupling protein-3 in skeletal muscle during exercise: a potential antioxidant function. Free Radic Biol Med,2009.46(2):p.138-45.
108. Mozo, J., et al., Expression of UCP3 in CHO cells does not cause uncoupling, but controls mitochondrial activity in the presence of glucose. Biochem J,2006.393(Pt 1):p. 431-9.
109. Gerber, L.K., B.J. Aronow, and M.A. Matlib, Activation of a novel long-chain free fatty acid generation and export system in mitochondria of diabetic rat hearts. Am J Physiol Cell Physiol,2006.291(6):p. C1198-207.
110. Himms-Hagen, J. and M.E. Harper, Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates:an hypothesis. Exp Biol Med (Maywood),2001.226(2):p.78-84.
111. Moore, G.B., et al., Overexpression of UCP-3 in skeletal muscle of mice results in increased expression of mitochondrial thioesterase mRNA. Biochem Biophys Res Commun,2001.283(4):p.785-90.
112. Moreno, M., et al., Fasting, lipid metabolism, and triiodothyronine in rat gastrocnemius muscle:interrelated roles of uncoupling protein 3, mitochondrial thioesterase, and coenzyme Q. FASEB J,2003.17(9):p.1112-4.
113. McGarry, J.D. and N.F. Brown, The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem,1997.244(1):p.1-14.
114. Kerner, J. and C. Hoppel, Fatty acid import into mitochondria. Biochim Biophys Acta, 2000.1486(1):p.1-17.
115. Declercq, P.E., et al., Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. I. Use of inhibitors. J Biol Chem,1987.262(20):p. 9812-21.
116. Cabrero, A., et al., Increased reactive oxygen species production down-regulates peroxisome proliferator-activated alpha pathway in C2C12 skeletal muscle cells. J Biol Chem,2002.277(12):p.10100-7.
117. Schrauwen, P., W.H. Saris, and M.K. Hesselink, An alternative function for human uncoupling protein 3:protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix. FASEB J,2001.15(13):p.2497-502.
118. Schrauwen, P. and M.K. Hesselink, The role of uncoupling protein 3 in fatty acid metabolism:protection against lipotoxicity? Proc Nutr Soc,2004.63(2):p.287-92.
119. Hamilton, J.A. and F. Kamp, How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? Diabetes,1999.48(12):p.2255-69.
120. Seifert, E.L., et al., Essential role for uncoupling protein-3 in mitochondrial adaptation to fasting but not in fatty acid oxidation or fatty acid anion export. J Biol Chem,2008. 283(37):p.25124-31.
121. Adams, J.M.,2nd, et al., Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes,2004.53(1):p.25-31.
122. Itani, S.I., et al., Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes,2002.51(7):p. 2005-11.
123. Li, Y., et al., UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells. PLoS One,2008.3(1):p. e1397.
124. Schrauwen, P., et al., Reduced skeletal muscle uncoupling protein-3 content in prediabetic subjects and type 2 diabetic patients:restoration by rosiglitazone treatment. J Clin Endocrinol Metab,2006.91(4):p.1520-5.
125. Huppertz, C., et al., Uncoupling protein 3 (UCP3) stimulates glucose uptake in muscle cells through a phosphoinositide 3-kinase-dependent mechanism. J Biol Chem,2001. 276(16):p.12520-9.
126. Pedersen, S.B., et al., Regulation of uncoupling protein (UCP) 2 and 3 in adipose and muscle tissue by fasting and growth hormone treatment in obese humans. Int J Obes Relat Metab Disord,2000.24(8):p.968-75.
127. Esterbauer, H., et al., Uncoupling protein-3 gene expression:reduced skeletal muscle mRNA in obese humans during pronounced weight loss. Diabetologia,1999.42(3):p. 302-9.
128. Hwang, C.S. and M.D. Lane, Up-regulation of uncoupling protein-3 by fatty acid in C2C12 myotubes. Biochem Biophys Res Commun,1999.258(2):p.464-9.
129. Sbraccia, P., et al., Relationship between plasma free fatty acids and uncoupling protein-3 gene expression in skeletal muscle of obese subjects:in vitro evidence of a causal link. Clin Endocrinol (Oxf),2002.57(2):p.199-207.
130. Cabrero, A., et al., Down-regulation of uncoupling protein-3 and-2 by thiazolidinediones in C2C12 myotubes. FEBS Lett,2000.484(1):p.37-42.
131. Costello, A., S. Gray, and R. Donnelly, Effects of rosiglitazone and oleic acid on UCP-3 expression in L6 myotubes. Diabetes Obes Metab,2003.5(2):p.136-8.
132. Nagase, I., et al., Up-regulation of uncoupling protein 3 by thyroid hormone, peroxisome proliferator-activated receptor ligands and 9-cis retinoic acid in L6 myotubes. FEBS Lett, 1999.461(3):p.319-22.
133. Son, C., et al., Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes. Endocrinology,2001.142(10):p.4189-94.
134. Jones, T.E., et al., Exercise induces an increase in muscle UCP3 as a component of the increase in mitochondrial biogenesis. Am J Physiol Endocrinol Metab,2003.284(1):p. E96-101.
135. Boss, O., et al., Effect of endurance training on mRNA expression of uncoupling proteins 1,2, and 3 in the rat. FASEB J,1998.12(3):p.335-9.
136. Fernstrom, M., M. Tonkonogi, and K. Sahlin, Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle. J Physiol,2004.554(Pt 3):p.755-63.
137. Schrauwen, P., et al., Skeletal muscle UCP2 and UCP3 expression in trained and untrained male subjects. Int J Obes Relat Metab Disord,1999.23(9):p.966-72.
138. Kliewer, S.A., et al., Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A,1994.91(15):p. 7355-9.
139. Qi, C., Y. Zhu, and J.K. Reddy, Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys,2000.32 Spring:p.187-204.
140. Abbott, B.D., Review of the expression of peroxisome proliferator-activated receptors alpha (PPAR alpha), beta (PPAR beta), and gamma (PPAR gamma) in rodent and human development. Reprod Toxicol,2009.27(3-4):p.246-57.
141. Feige, J.N., et al., Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand. J Biol Chem,2005.280(18):p.17880-90.
142. Forman, B.M., J. Chen, and R.M. Evans, Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A,1997.94(9):p.4312-7.
143. Gervois, P., J.C. Fruchart, and B. Staels, Drug Insight:mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab,2007.3(2):p.145-56.
144. Tu, N., et al., Molecular cloning and functional characterization of the promoter region of the human uncoupling protein-2 gene. Biochem Biophys Res Commun,1999.265(2): p.326-34.
145. Solanes, G., et al., Functional relationship between MyoD and peroxisome proliferator-activated receptor-dependent regulatory pathways in the control of the human uncoupling protein-3 gene transcription. Mol Endocrinol,2003.17(10):p. 1944-58.
146. Pedraza, N., et al., Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation:fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. Diabetes,2000.49(7):p.1224-30.
147. Young, M.E., et al., Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J,2001.15(3):p. 833-45.
148. Cabrero, A., et al., Peroxisome proliferator-activated receptor alpha (PPARalpha) activators, bezafibrate and Wy-14,643, increase uncoupling protein-3 mRNA levels without modifying the mitochondrial membrane potential in primary culture of rat preadipocytes. Arch Biochem Biophys,2000.380(2):p.353-9.
149. Hardie, D.G, S.A. Hawley, and J.W. Scott, AMP-activated protein kinase--development of the energy sensor concept. J Physiol,2006.574(Pt 1):p.7-15.
150. Steinberg, G.R. and B.E. Kemp, AMPK in Health and Disease. Physiol Rev,2009.89(3): p.1025-78.
151. Zheng, D., et al., Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol,2001.91(3):p.1073-83.
152. Stoppani, J., et al., AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle. Am J Physiol Endocrinol Metab,2002.283(6):p. E1239-48.
153. Chabowski, A., et al., Prolonged AMPK activation increases the expression of fatty acid transporters in cardiac myocytes and perfused hearts. Mol Cell Biochem,2006.288(1-2): p.201-12.
154. Barnes, B.R., et al., Changes in exercise-induced gene expression in 5'-AMP-activated protein kinase gammai-null and gamma3 R225Q transgenic mice. Diabetes,2005. 54(12):p.3484-9.
155. Corton, J.M., et al.,5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem,1995.229(2): p.558-65.
156. Pedersen, S.B., et al., Insulin and contraction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal muscle in vitro. Biochem Biophys Res Commun,2001.283(1): p.19-25.
157. Putman, C.T., et al., AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions. J Physiol, 2003.551(Pt 1):p.169-78.
158. Suwa, M., H. Nakano, and S. Kumagai, Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J Appl Physiol,2003. 95(3):p.960-8.
159. Li, J.B. and L.S. Jefferson, Influence of amino acid availability on protein turnover in perfused skeletal muscle. Biochim Biophys Acta,1978.544(2):p.351-9.
160. Hong, S.O. and D.K. Layman, Effects of leucine on in vitro protein synthesis and degradation in rat skeletal muscles. J Nutr,1984.114(7):p.1204-12.
161. Anthony, J.C., et al., Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J Nutr, 2000.130(2):p.139-45.
162. Anthony, J.C., et al., Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. Diabetes,2002.51(4):p.928-36.
163. Crozier, S.J., et al., Oral leucine administration stimulates protein synthesis in rat skeletal muscle. J Nutr,2005.135(3):p.376-82.
164. Kimball, S.R., et al., Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem,1999.274(17):p.11647-52.
165. Sun, X. and M.B. Zemel, Leucine modulation of mitochondrial mass and oxygen consumption in skeletal muscle cells and adipocytes. Nutr Metab (Lond),2009.6:p.26.
166. Volpers, C. and S. Kochanek, Adenoviral vectors for gene transfer and therapy. J Gene Med,2004.6 Suppl 1:p. S164-71.
167. Danthinne, X. and M.J. Imperiale, Production of first generation adenovirus vectors:a review. Gene Ther,2000.7(20):p.1707-14.
168. Engelhardt, J.F., et al., Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc Natl Acad Sci U S A,1994.91(13):p.6196-200.
169. Armentano, D., et al., Characterization of an adenovirus gene transfer vector containing an E4 deletion. Hum Gene Ther,1995.6(10):p.1343-53.
170. Yang, Y., et al., Cellular immunity to viral antigens limits EI-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A,1994.91(10):p.4407-11.
171. Mitani, K., et al., Rescue, propagation, and partial purification of a helper virus-dependent adenovirus vector. Proc Natl Acad Sci U S A,1995.92(9):p.3854-8.
172. Kochanek, S., G. Schiedner, and C. Volpers, High-capacity'gutless'adenoviral vectors. Curr Opin Mol Ther,2001.3(5):p.454-63.
173. Morsy, M.A., et al., An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc Natl Acad Sci U S A, 1998.95(14):p.7866-71.
174. Schiedner, G., et al., Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet,1998. 18(2):p.180-3.
175. Luo, J., et al., A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc,2007.2(5):p.1236-47.
176. Mao, X., et al., APPLI binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol,2006.8(5):p.516-23.
177. Chomczynski, P. and N. Sacchi, Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem,1987.162(1):p. 156-9.
178. Negre-Salvayre, A., et al., Detection of intracellular reactive oxygen species in cultured cells using fluorescent probes. Methods Enzymol,2002.352:p.62-71.
179. Tsakiridis, T., M. Vranic, and A. Klip, Disassembly of the actin network inhibits insulin-dependent stimulation of glucose transport and prevents recruitment of glucose transporters to the plasma membrane. J Biol Chem,1994.269(47):p.29934-42.
180. Bieber, L.L., T. Abraham, and T. Helmrath, A rapid spectrophotometric assay for carnitine palmitoyltransferase. Anal Biochem,1972.50(2):p.509-18.
181. Rubi, B., et al., Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase Ⅰ in INS1E cells:effects on cell metabolism and insulin secretion. Biochem J,2002.364(Pt 1):p.219-26.
182. Shimokawa, T., et al., Transcriptional regulation of muscle-specific genes during myoblast differentiation. Biochem Biophys Res Commun,1998.246(1):p.287-92.
183. Eaton, S., Control of mitochondrial beta-oxidation flux. Prog Lipid Res,2002.41(3):p. 197-239.
184. Svensson, L.T., et al., Molecular cloning and characterization of a mitochondrial peroxisome proliferator-induced acyl-CoA thioesterase from rat liver. Biochem J,1998. 329 (Pt 3):p.601-8.
185. Brass, E.P., Pharmacokinetic considerations for the therapeutic use of carnitine in hemodialysis patients. Clin Ther,1995.17(2):p.176-85; discussion 175.
186. Brooks, D.E. and J.E. McIntosh, Turnover of carnitine by rat tissues. Biochem J,1975. 148(3):p.439-45.
187. Cederblad, G., S. Lindstedt, and K. Lundholm, Concentration of carnitine in human muscle tissue. Clin Chim Acta,1974.53(3):p.311-21.
188. Engel, A.G. and C. Angelini, Carnitine deficiency of human skeletal muscle with associated lipidstorage myopathy:a new syndrome. Science,1973.179(76):p.899-902.
189. Stephens, F.B., et al., An acute increase in skeletal muscle carnitine content alters fuel metabolism in resting human skeletal muscle. J Clin Endocrinol Metab,2006.91(12):p. 5013-8.
190. Skulachev, V.P., Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett,1991.294(3):p.158-62.
191. Garlid, K.D., M. Jaburek, and P. Jezek, The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett,1998.438(1-2):p.10-4.
192. Jezek, P., et al., Transport of anions and protons by the mitochondrial uncoupling protein and its regulation by nucleotides and fatty acids. A new look at old hypotheses. J Biol Chem,1994.269(42):p.26184-90.
193. Severin, F.F., et al., Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc Natl Acad Sci U S A,2010.107(2):p.663-8.
194. Adams, S.H., et al., Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr,2009.139(6):p.1073-81.
195. Sebastian, D., et al., CPT I overexpression protects L6E9 muscle cells from fatty acid-induced insulin resistance. Am J Physiol Endocrinol Metab,2007.292(3):p. E677-86.
196. Randle, P.J., et al., The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet,1963.1(7285):p.785-9.
197. Bouzakri, K., et al., Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle. Diabetes,2008.57(6):p.1508-16.
198. Koves, T.R., et al., Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab,2008.7(1):p.45-56.
199. Shulman, G.I., Cellular mechanisms of insulin resistance. J Clin Invest,2000.106(2):p. 171-6.
200. Roden, M., et al., Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest,1996.97(12):p.2859-65.
201. Gilde, A.J. and M. Van Bilsen, Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand,2003. 178(4):p.425-34.
202. Aoyama, T., et al., Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem,1998.273(10):p.5678-84.
203. Leone, T.C., C.J. Weinheimer, and D.P. Kelly, A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response:the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A,1999.96(13):p.7473-8.
204. Brun, S., et al., Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle:a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. Diabetes,1999.48(6):p.1217-22.
205. Winder, W.W., et al., Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol,2000.88(6):p.2219-26.
206. Merrill, G.F., et al., AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol,1997.273(6 Pt 1):p. E1107-12.
207. Ruderman, N.B., et al., Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol, 1999.276(1 Pt 1):p. E1-E18.