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Mediators of Inflammation
Volume 2013, Article ID 135698, 13 pages
http://dx.doi.org/10.1155/2013/135698
Review Article

Mitochondrial Dysfunction: A Basic Mechanism in Inflammation-Related Non-Communicable Diseases and Therapeutic Opportunities

1Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, carrer Sant Llorenç 21, 43201 Reus, Spain
2Catalan Institute of Oncology and Girona Biomedical Research Institute, Avda de Francia s/n, 1707 Girona, Spain

Received 5 December 2012; Revised 1 February 2013; Accepted 1 February 2013

Academic Editor: Fábio Santos Lira

Copyright © 2013 Anna Hernández-Aguilera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. K. Strong, C. Mathers, S. Leeder, and R. Beaglehole, “Preventing chronic diseases: how many lives can we save?” The Lancet, vol. 366, no. 9496, pp. 1578–1582, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. M. Cecchini, F. Sassi, J. A. Lauer, Y. Y. Lee, V. Guajardo-Barron, and D. Chisholm, “Tackling of unhealthy diets, physical inactivity, and obesity: health effects and cost-effectiveness,” The Lancet, vol. 376, no. 9754, pp. 1775–1784, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. T. A. Gaziano, G. Galea, and K. S. Reddy, “Scaling up interventions for chronic disease prevention: the evidence,” The Lancet, vol. 370, no. 9603, pp. 1939–1946, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. E. A. H. Sims, “Are there persons who are obese, but metabolically healthy?” Metabolism, vol. 50, no. 12, pp. 1499–1504, 2001. View at Publisher · View at Google Scholar
  5. N. Stefan, K. Kantartzis, J. Machann et al., “Identification and characterization of metabolically benign obesity in humans,” Archives of Internal Medicine, vol. 168, no. 15, pp. 1609–1616, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. G. Iacobellis, M. C. Ribaudo, A. Zappaterreno, C. V. Iannucci, and F. Leonetti, “Prevalence of uncomplicated obesity in an Italian obese population,” Obesity Research, vol. 13, no. 6, pp. 1116–1122, 2005. View at Google Scholar · View at Scopus
  7. A. Rull, J. Camps, C. Alonso-Villaverde, and J. Joven, “Insulin resistance, inflammation, and obesity: role of monocyte chemoattractant protein-1 (orCCL2) in the regulation of metabolism,” Mediators of Inflammation, vol. 2010, Article ID 326580, 11 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. J. B. Meigs, I. Lipinska, S. Kathiresan et al., “Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the framingham heart study,” Circulation, vol. 116, no. 11, pp. 1234–1241, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. D. Dowell and T. A. Farley, “Prevention of non-communicable diseases in New York City,” The Lancet, vol. 380, no. 9855, pp. 1787–1792, 2012. View at Publisher · View at Google Scholar
  10. D. M. Arduíno, A. R. Esteves, and S. M. Cardoso, “Mitochondria drive autophagy pathology via microtubule disassembly: a new hypothesis for Parkinson disease,” Autophagy, vol. 9, no. 1, pp. 112–114, 2013. View at Google Scholar
  11. H. Kumar, H. W. Lim, S. V. More et al., “The role of free radicals in the aging brain and Parkinson's disease: convergence and parallelism,” International Journal of Molecular Science, vol. 13, no. 8, pp. 10478–10504, 2012. View at Publisher · View at Google Scholar
  12. G. Medina-Gómez, “Mitochondria and endocrine function of adipose tissue,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 26, no. 6, pp. 791–804, 2012. View at Publisher · View at Google Scholar
  13. G. Pagano, G. Castello, and F. V. Pallardó, “Sjøgren's syndrome-associated oxidative stress and mitochondrial dysfunction: prospects for chemoprevention trials,” Free Radical Research, vol. 47, no. 2, pp. 71–73, 2013. View at Publisher · View at Google Scholar
  14. J. Ouyang, M. Wu, C. Huang, L. Cao, and G. Li, “Overexpression of oxidored-nitro domain containing protein 1 inhibits human nasopharyngeal carcinoma and cervical cancer cell proliferation and induces apoptosis: involvement of mitochondrial apoptotic pathways,” Oncology Reports, vol. 29, no. 1, pp. 79–86, 2013. View at Google Scholar
  15. L. D. Osellame, T. S. Blacker, and M. R. Duchen, “Cellular and molecular mechanisms of mitochondrial function,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 26, no. 6, pp. 711–723, 2012. View at Publisher · View at Google Scholar
  16. I. Enache, A. L. Charles, J. Bouitbir et al., “Skeletal muscle mitochondrial dysfunction precedes right ventricular impairment in experimental pulmonary hypertension,” Molecular and Cellular Biochemistry, vol. 373, no. 1-2, pp. 161–170, 2013. View at Publisher · View at Google Scholar
  17. L. W. Chol, “Metabolic syndrome,” Singapore Medical Journal, vol. 52, no. 11, pp. 779–785, 2011. View at Google Scholar
  18. M. R. Souza, F. D. Mde, J. E. Medeiros-Filho, and M. S. Araújo, “Metabolic syndrome and risk factors for non-alcoholic fatty liver disease,” Arquivos de Gastroenterologia, vol. 49, no. 1, pp. 89–96, 2012. View at Google Scholar
  19. M. S. Mirza, “Obesity, visceral fat and NAFLD: querying the role of adipokines in the progression of nonalcoholic fatty liver disease,” ISRN Gastroenterology, vol. 2011, Article ID 592404, 11 pages, 2011. View at Publisher · View at Google Scholar
  20. G. Tarantino, S. Savastano, and A. Colao, “Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance,” World Journal of Gastroenterology, vol. 16, no. 38, pp. 4773–4783, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. C. Vernochet and C. R. Kahn, “Mitochondria, obesity and aging,” Aging, vol. 4, no. 12, pp. 1–2, 2012. View at Google Scholar
  22. F. Pintus, G. Floris, and A. Rufini, “Nutrient availability links mitocondria, apoptosis and obesity,” Aging, vol. 4, no. 11, pp. 1–8, 2012. View at Google Scholar
  23. M. M. Rogge, “The role of impaired mitochondrial lipid oxidation in obesity,” Biological Research for Nursing, vol. 10, no. 4, pp. 356–373, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Vinaixa, M. A. Rodríguez, A. Rull et al., “Metabolomic assessment of the effect of dietary cholesterol in the progressive development of fatty liver disease,” Journal of Proteome Research, vol. 9, no. 5, pp. 2527–2538, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. A. Rull, M. Vinaixa, M. Ángel Rodríguez et al., “Metabolic phenotyping of genetically modified mice: an NMR metabonomic approach,” Biochimie, vol. 91, no. 8, pp. 1053–1057, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Joven, A. Rull, N. Ferré et al., “The results in rodent models of atherosclerosis are not interchangeable. The influence of diet and strain,” Atherosclerosis, vol. 195, no. 2, pp. e85–e92, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. M. Tous, N. Ferré, J. Camps, F. Riu, and J. Joven, “Feeding apolipoprotein E-knockout mice with cholesterol and fat enriched diets may be a model of non-alcoholic steatohepatitis,” Molecular and Cellular Biochemistry, vol. 268, no. 1-2, pp. 53–58, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. P. Lindström, “β-cell function in obese-hyperglycemic mice [ob/ob mice],” Advances in Experimental Medicine and Biology, vol. 654, pp. 463–477, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. S. de Ferranti and D. Mozaffarian, “The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences,” Clinical Chemistry, vol. 54, no. 6, pp. 945–955, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Xu, X. Ma, B. Cui, X. Li, G. Ning, and S. Wang, “Selection of reference genes for qRT-PCR in high fat diet-induced hepatic steatosis mice model,” Molecular Biotechnology, vol. 48, no. 3, pp. 255–262, 2011. View at Publisher · View at Google Scholar
  31. M. V. Machado, J. Coutinho, F. Carepa, A. Costa, H. Proença, and H. Cortez-Pinto, “How adiponectin, leptin, and ghrelin orchestrate together and correlate with the severity of nonalcoholic fatty liver disease,” European Journal of Gastroenterology and Hepatology, vol. 24, no. 10, pp. 1166–1172, 2012. View at Publisher · View at Google Scholar
  32. J. C. Cohen, J. D. Horton, and H. H. Hobbs, “Human fatty liver disease: old questions and new insights,” Science, vol. 332, no. 6037, pp. 1519–1523, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. M. J. Pagliassotti, “Endoplasmic reticulum stress in nonalcoholic fatty liver disease,” Annual Review of Nutrition, vol. 32, pp. 17–33, 2012. View at Publisher · View at Google Scholar
  34. J. V. Neel, “Diabetes mellitus a “thrifty” genotype rendered detrimental by ‘progress’?” The American Journal of Human Genetics, vol. 14, pp. 352–353, 1962. View at Google Scholar
  35. J. V. Neel, “Update to ‘The study of natural selection in primitive and civilized human populations’,” Human Biology, vol. 61, no. 5-6, pp. 811–823, 1989. View at Google Scholar · View at Scopus
  36. A. R. Frisancho, “Reduced rate of fat oxidation: a metabolic pathway to obesity in the developing nations,” The American Journal of Human Biology, vol. 15, no. 4, pp. 522–532, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. J. R. Speakman, “A novel non-adaptive scenario explaining the genetic pre-disposition to obesity: the “predation release” hypothesis,” Cell Metabolism, vol. 6, no. 1, pp. 5–12, 2007. View at Publisher · View at Google Scholar
  38. J. R. Speakman and S. O'Rahilly, “Fat: an evolving issue,” Disease Models and Mechanisms, vol. 5, no. 5, pp. 569–573, 2012. View at Publisher · View at Google Scholar
  39. B. Rius, C. López-Vicario, A. González-Périz et al., “Resolution of inflammation in obesity-induced liver disease,” Frontiers in Immunology, vol. 3, article 257, 2012. View at Publisher · View at Google Scholar
  40. A. Paul, L. Calleja, J. Camps et al., “The continuous administration of aspirin attenuates atherosclerosis in apolipoprotein E-deficient mice,” Life Sciences, vol. 68, no. 4, pp. 457–465, 2000. View at Publisher · View at Google Scholar · View at Scopus
  41. M. Tous, N. Ferré, A. Rull et al., “Dietary cholesterol and differential monocyte chemoattractant protein-1 gene expression in aorta and liver of apo E-deficient mice,” Biochemical and Biophysical Research Communications, vol. 340, no. 4, pp. 1078–1084, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. L. Masana, M. Camprubi, P. Sarda, R. Sola, J. Joven, and P. R. Turner, “The mediterranean-type diet: is there a need for further modification?” The American Journal of Clinical Nutrition, vol. 53, no. 4, pp. 886–889, 1991. View at Google Scholar · View at Scopus
  43. A. P. Rolo, J. S. Teodoro, and C. M. Palmeira, “Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis,” Free Radical Biology and Medicine, vol. 52, no. 1, pp. 59–69, 2012. View at Publisher · View at Google Scholar
  44. B. Mlinar and J. Marc, “New insights into adipose tissue dysfunction in insulin resistance,” Clinical Chemistry and Laboratory Medicine, vol. 29, no. 12, pp. 1925–1935, 2011. View at Google Scholar
  45. C. N. Lumeng, J. L. Bodzin, and A. R. Saltiel, “Obesity induces a phenotypic switch in adipose tissue macrophage polarization,” Journal of Clinical Investigation, vol. 117, no. 1, pp. 175–184, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. M. E. Shaul, G. Bennett, K. J. Strissel, A. S. Greenberg, and M. S. Obin, “Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet—induced obesity in mice,” Diabetes, vol. 59, no. 5, pp. 1171–1181, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. J. M. Wentworth, G. Naselli, W. A. Brown et al., “Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity,” Diabetes, vol. 59, no. 7, pp. 1648–1656, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. A. Rull, R. Beltrán-Debón, G. Aragonès et al., “Expression of cytokine genes in the aorta is altered by the deficiency in MCP-1: effect of a high-fat, high-cholesterol diet,” Cytokine, vol. 50, no. 2, pp. 121–128, 2010. View at Publisher · View at Google Scholar
  49. M. L. Batista, S. B. Peres, M. E. McDonald et al., “Adipose tissue inflammation and cancer cachexia: possible role of nuclear transcription factors,” Cytokine, vol. 57, no. 1, pp. 9–16, 2012. View at Publisher · View at Google Scholar
  50. A. Rull, J. C. Escolà-Gil, J. Julve et al., “Deficiency in monocyte chemoattractant protein-1 modifies lipid and glucose metabolism,” Experimental and Molecular Pathology, vol. 83, no. 3, pp. 361–366, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. B. Coll, C. Alonso-Villaverde, and J. Joven, “Monocyte chemoattractant protein-1 and atherosclerosis: Is there room for an additional biomarker?” Clinica Chimica Acta, vol. 383, no. 1-2, pp. 21–29, 2007. View at Publisher · View at Google Scholar · View at Scopus
  52. B. Westermann, “Mitochondrial fusion and fission in cell life and death,” Nature Reviews Molecular Cell Biology, vol. 11, no. 12, pp. 872–884, 2010. View at Publisher · View at Google Scholar · View at Scopus
  53. D. C. Chan, “Mitochondrial fusion and fission in mammals,” Annual Review of Cell and Developmental Biology, vol. 22, pp. 79–99, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. D. H. Margineantu, W. G. Cox, L. Sundell, S. W. Sherwood, J. M. Beechem, and R. A. Capaldi, “Cell cycle dependent morphology changes and associated mitochondrial DNA redistribution in mitochondria of human cell lines,” Mitochondrion, vol. 1, no. 5, pp. 425–435, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. A. E. Frazier, C. Kiu, D. Stojanovski, N. J. Hoogenraad, and M. T. Ryan, “Mitochondrial morphology and distribution in mammalian cells,” Biological Chemistry, vol. 387, no. 12, pp. 1551–1558, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. B. Westermann, “Bioenergetic role of mitochondrial fusion and fission,” Biochimica et Biophysica Acta, vol. 1817, no. 10, pp. 1833–1838, 2012. View at Publisher · View at Google Scholar
  57. J. C. Chang, S. J. Kou, W. T. Lin, and C. S. Liu, “Regulatory role of mitochondria in oxidative stress and atherosclerosis,” World Journal of Cardiology, vol. 2, no. 6, pp. 150–159, 2010. View at Publisher · View at Google Scholar
  58. D. C. Chan, “Mitochondria: dynamic organelles in disease, aging, and development,” Cell, vol. 125, no. 7, pp. 1241–1252, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. K. C. Fearon, D. J. Glass, and D. C. Guttridge, “Cancer cachexia: mediators, signaling, and metabolic pathways,” Cell Metabolism, vol. 16, no. 2, pp. 153–166, 2012. View at Publisher · View at Google Scholar
  60. F. S. Lira, L. C. Carnevali, N. E. Zanchi, R. V. T. Santos, J. M. Lavoie, and M. Seelaender, “Exercise intensity modulation of hepatic lipid metabolism,” Journal of Nutrition and Metabolism, vol. 2012, Article ID 809576, 8 pages, 2012. View at Publisher · View at Google Scholar
  61. S. Lokireddy, I. W. Wijesoma, S. Teng et al., “The ubiquitin ligase mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli,” Cell Metabolism, vol. 16, no. 5, pp. 613–624, 2012. View at Publisher · View at Google Scholar
  62. M. Banasch, M. Ellrichmann, A. Tannapfel, W. E. Schmidt, and O. Goetze, “The non-invasive 13C-methionine breath test detects hepatic mitochondrial dysfunction as a marker of disease activity in non-alcoholic steatohepatitis,” European Journal of Medical Research, vol. 16, no. 6, pp. 258–264, 2011. View at Google Scholar · View at Scopus
  63. W. Dröge and H. M. Schipper, “Oxidative stress and aberrant signaling in aging and cognitive decline,” Aging Cell, vol. 6, no. 3, pp. 361–370, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. M. E. Witte, J. J. G. Geurts, H. E. de Vries, P. van der Valk, and J. van Horssen, “Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration?” Mitochondrion, vol. 10, no. 5, pp. 411–418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. J. A. Menendez, S. Cufi, C. Oliveras-Ferraros, L. Vellon, J. Joven, and A. Vazquez-Martin, “Gerosuppressant metformin: less is more,” Aging, vol. 3, no. 4, pp. 348–362, 2011. View at Google Scholar
  66. S. I. Rattan, “Anti-ageing strategies: prevention or therapy? Showing ageing from within,” EMBO Reports, vol. 6, pp. S25–S29, 2005. View at Google Scholar · View at Scopus
  67. V. B. Saprunova, M. A. Lelekova, N. G. Kolosova, and L. E. Bakeeva, “SkQ1 slows development of age-dependent destructive processes in retina and vascular layer of eyes of wistar and OXYS rats,” Biochemistry, vol. 77, no. 6, pp. 648–658, 2012. View at Publisher · View at Google Scholar
  68. T. F. Liu, C. M. Brown, M. El Gazzar et al., “Fueling the flame: bioenergy couples metabolism and inflammation,” Journal of Leukocyte Biology, vol. 92, no. 3, pp. 499–507, 2012. View at Publisher · View at Google Scholar
  69. E. Profumo, B. Buttari, L. Petrone et al., “Redox imbalance of red blood cells impacts T lymphocyte homeostasis: implication in carotid atherosclerosis,” Journal of Thrombosis and Haemostasis, vol. 106, no. 6, pp. 1117–1126, 2011. View at Publisher · View at Google Scholar
  70. C. M. Kusminski, W. L. Holland, K. Sun et al., “MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptative process that preserves insulin sensitivity in obesity,” Nature Medicine, vol. 18, no. 10, pp. 1539–1549, 2012. View at Publisher · View at Google Scholar
  71. A. Zorzano, M. Liesa, and M. Palacín, “Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 10, pp. 1846–1854, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Aguer and M. E. Harper, “Skeletal muscle mitochondrial energetics in obesity and type 2 diabetes mellitus: endocrine aspects,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 26, no. 6, pp. 805–819, 2012. View at Publisher · View at Google Scholar
  73. Z. A. Ma, “The role of peroxidation of mitochondrial membrane phospholipids in pancreatic β-cell failure,” Current Diabetes Reviews, vol. 8, no. 1, pp. 69–75, 2012. View at Publisher · View at Google Scholar
  74. C. Tang, K. Koulajian, I. Schuiki et al., “Glucose-induced beta cell dysfunction in vivo in rats: link between oxidative stress and endoplasmic reticulum stress,” Diabetologia, vol. 55, no. 5, pp. 1366–1379, 2012. View at Publisher · View at Google Scholar
  75. A. Lde. Brondani, T. S. Assmann, G. C. Duarte, J. L. Gross, L. H. Canani, and D. Crispim, “The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 56, no. 4, pp. 215–225, 2012. View at Google Scholar
  76. A. Fedorenko, P. V. Lishko, and Y. Kirichok, “Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria,” Cell, vol. 151, no. 2, pp. 400–413, 2012. View at Publisher · View at Google Scholar
  77. B. Cannon and J. Nedergaard, “Cell biology: neither brown nor white,” Nature, vol. 488, no. 7411, pp. 286–287, 2012. View at Publisher · View at Google Scholar
  78. I. Grattagliano, O. de Bari, T. C. Bernardo, P. J. Oliveira, D. Q. Wang, and P. Portincasa, “Role of mitochondria in nonalcoholic fatty liver disease—from origin to propagation,” Clinical Biochemistry, vol. 45, no. 9, pp. 610–618, 2012. View at Publisher · View at Google Scholar
  79. G. Serviddio, F. Bellanti, G. Vendemiale, and E. Altomare, “Mitochondrial dysfunction in nonalcoholic steatohepatitis,” Expert Review of Gastroenterology and Hepatology, vol. 5, no. 2, pp. 233–244, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. N. C. Sadler, T. E. Angel, M. P. Lewis et al., “Activity-based protein profiling reveals mitochondrial oxidative enzyme impairment and restoration in diet-induced obese mice,” PLoS ONE, vol. 7, no. 10, Article ID e47996, 2012. View at Publisher · View at Google Scholar
  81. M. Carrer, N. Liu, C. E. Grueter et al., “Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 38, pp. 15330–15335, 2012. View at Publisher · View at Google Scholar
  82. A. D. Karelis, M. Faraj, J. P. Bastard et al., “The metabolically healthy but obese individual presents a favorable inflammation profile,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 7, pp. 4145–4150, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. C. M. Kusminski and P. E. Scherer, “Mitochondrial dysfunction in white adipose tissue,” Trends in Endocrinology and Metabolism, vol. 23, no. 9, pp. 435–443, 2012. View at Publisher · View at Google Scholar
  84. A. Zorzano, M. I. Hernández-Alvarez, M. Palacín, and G. Mingrone, “Alterations in the mitochondrial regulatory pathways constituted by the nuclear co-factors PGC-1α or PGC-1β and mitofusin 2 in skeletal muscle in type 2 diabetes,” Biochimica et Biophysica Acta, vol. 1797, no. 6-7, pp. 1028–1033, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. A. Zorzano, D. Sebastián, J. Segalés, and M. Palacín, “The molecular machinery of mitochondrial fusion and fission: an opportunity for drug discovery?” Current Opinion in Drug Discovery and Development, vol. 12, no. 5, pp. 597–606, 2009. View at Google Scholar · View at Scopus
  86. X. J. Chen and R. A. Butow, “The organization and inheritance of the mitochondrial genome,” Nature Reviews Genetics, vol. 6, no. 11, pp. 815–825, 2005. View at Publisher · View at Google Scholar
  87. A. M. Distler, J. Kerner, and C. L. Hoppel, “Proteomics of mitochondrial inner and outer membranes,” Proteomics, vol. 8, no. 19, pp. 4066–4082, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. L. Galluzzi, I. Vitale, J. M. Abrams et al., “Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012,” Cell Death and Differentiation, vol. 19, pp. 107–120, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. N. Joza, G. Y. Oudit, D. Brown et al., “Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy,” Molecular and Cellular Biology, vol. 25, no. 23, pp. 10261–10272, 2005. View at Publisher · View at Google Scholar · View at Scopus
  90. J. R. Speakman and S. E. Mitchell, “Caloric restriction,” Molecular Aspects of Medicine, vol. 32, no. 3, pp. 159–221, 2011. View at Publisher · View at Google Scholar
  91. A. Raffaello and R. Rizzuto, “Mitochondrial longevity pathways,” Biochimica et Biophysica Acta, vol. 1813, no. 1, pp. 260–268, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. N. Alkhouri, A. Gornicka, M. P. Berk et al., “Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis,” The Journal of Biological Chemistry, vol. 285, no. 5, pp. 3428–3438, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. I. P. Salt and T. M. Palmer, “Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation,” Expert Opinion on Investigational Drugs, vol. 21, no. 8, pp. 1155–1167, 2012. View at Publisher · View at Google Scholar
  94. J. G. Boyle, P. J. Logan, G. C. Jones et al., “AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study,” Diabetologia, vol. 54, no. 7, pp. 1799–1809, 2011. View at Publisher · View at Google Scholar · View at Scopus
  95. J. E. Sullivan, K. J. Brocklehurst, A. E. Marley, F. Carey, D. Carling, and R. K. Beri, “Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase,” FEBS Letters, vol. 353, no. 1, pp. 33–36, 1994. View at Publisher · View at Google Scholar · View at Scopus
  96. W. Yin, J. Mu, and M. J. Birnbaum, “Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis in 3T3-L1 adipocytes,” The Journal of Biological Chemistry, vol. 278, no. 44, pp. 43074–43080, 2003. View at Publisher · View at Google Scholar · View at Scopus
  97. M. P. Gaidhu, S. Fediuc, and R. B. Ceddia, “5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes,” The Journal of Biological Chemistry, vol. 281, no. 36, pp. 25956–25964, 2006. View at Publisher · View at Google Scholar · View at Scopus
  98. M. P. Gaidhu, S. Fediuc, N. M. Anthony et al., “Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL,” Journal of Lipid Research, vol. 50, no. 4, pp. 704–715, 2009. View at Publisher · View at Google Scholar · View at Scopus
  99. A. T. Turer and P. E. Scherer, “Adiponectin: mechanistic insights and clinical implications,” Diabetologia, vol. 55, no. 9, pp. 2319–2326, 2012. View at Publisher · View at Google Scholar
  100. S. Galic, M. D. Fullerton, J. D. Schertzer et al., “Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity,” Journal of Clinical Investigation, vol. 121, no. 12, pp. 4903–4915, 2011. View at Publisher · View at Google Scholar
  101. R. Vila-Bedmar, M. Lorenzo, and S. Fernández-Veledo, “Adenosine 5′-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation,” Endocrinology, vol. 151, no. 3, pp. 980–992, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. O. Horakova, D. Medrikova, E. M. van Schothorst et al., “Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese mice,” PLoS ONE, vol. 7, no. 8, Article ID e43764, 2012. View at Publisher · View at Google Scholar
  103. V. T. To, T. P. Hüttl, R. Lang, K. Piotrowski, and K. G. Parhofer, “Changes in body weight, glucose homeostasis, lipid profiles, and metabolic syndrome after restrictive bariatric surgery,” Experimental and Clinical Endocrinology and Diabetes, vol. 120, no. 9, pp. 547–552, 2012. View at Publisher · View at Google Scholar
  104. H. M. Heneghan, S. Nissen, and P. R. Schauer, “Gastrointestinal surgery for obesity and diabetes: weight loss and control of hyperglycemia,” Current Atherosclerosis Reports, vol. 14, no. 6, pp. 579–587, 2012. View at Publisher · View at Google Scholar
  105. A. Luke, J. O’Neill, and D. Hardie, “Metabolism of inflammation limited by AMPK and pseudo-starvation,” Nature, vol. 493, pp. 346–355, 2013. View at Publisher · View at Google Scholar
  106. C. Finelli and G. Tarantino, “Is there any consensus as to what diet of lifestyle approach is the right one for NAFLD patients?” Journal of Gastrointestinal and Liver Diseases, vol. 21, pp. 293–302, 2012. View at Google Scholar
  107. J. Joven, J. Menéndez, L. Fernandez-Sender et al., “Metformin: a cheap and well-tolerated drug that provides benefits for viral infections,” HIV Medicine, 2012. View at Publisher · View at Google Scholar
  108. S. Del Barco, A. Vazquez-Martin, S. Cufí et al., “Metformin: multi-faceted protection against cancer,” Oncotarget, vol. 2, no. 12, pp. 896–917, 2011. View at Google Scholar
  109. B. Viollet, B. Guigas, N. Sanz Garcia, J. Leclerc, M. Foretz, and F. Andreelli, “Cellular and molecular mechanisms of metformin: an overview,” Clinical Science, vol. 122, no. 6, pp. 253–270, 2012. View at Publisher · View at Google Scholar
  110. S. Nair, A. M. Diehl, M. Wiseman, G. H. Farr, and R. P. Perrillo, “Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial,” Alimentary Pharmacology and Therapeutics, vol. 20, no. 1, pp. 23–28, 2004. View at Publisher · View at Google Scholar · View at Scopus
  111. A. Duseja, A. Das, R. K. Dhiman et al., “Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions,” Annals of Hepatology, vol. 6, no. 4, pp. 222–226, 2007. View at Google Scholar · View at Scopus
  112. J. W. Haukeland, Z. Konopsi, H. B. Eggesbo et al., “Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial,” Scandinavian Journal of Gastroenterology, vol. 44, no. 7, pp. 853–860, 2009. View at Google Scholar
  113. M. Foretz, S. Hébrard, J. Leclerc et al., “Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state,” Journal of Clinical Investigation, vol. 120, no. 7, pp. 2355–2369, 2010. View at Publisher · View at Google Scholar · View at Scopus
  114. M. R. Owen, E. Doran, and A. P. Halestrap, “Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain,” Biochemical Journal, vol. 348, no. 3, pp. 607–614, 2000. View at Publisher · View at Google Scholar · View at Scopus
  115. B. H. Ahn, H. S. Kim, S. Song et al., “A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 38, pp. 14447–14452, 2008. View at Publisher · View at Google Scholar · View at Scopus
  116. X. Kong, R. Wang, Y. Xue et al., “Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis,” PLoS ONE, vol. 5, no. 7, Article ID e11707, 2010. View at Publisher · View at Google Scholar · View at Scopus
  117. M. Buler, S. M. Aatsinki, V. Izzi, and J. Hakkola, “Metformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism,” PLoS ONE, vol. 7, no. 11, Article ID e49863, 2012. View at Publisher · View at Google Scholar
  118. P. W. Caton, N. K. Nayuni, J. Kieswich, N. Q. Khan, M. M. Yaqoob, and R. Corder, “Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5,” Journal of Endocrinology, vol. 205, no. 1, pp. 97–106, 2010. View at Publisher · View at Google Scholar · View at Scopus
  119. B. Corominas-Faja, R. Quirantes-Piné, C. Oliveras-Ferraros et al., “Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs,” Aging, vol. 4, no. 7, pp. 480–498, 2012. View at Google Scholar
  120. R. Beltrán-Debón, A. Rull, F. Rodríguez-Sanabria et al., “Continuous administration of polyphenols from aqueous rooibos (Aspalathus linearis) extract ameliorates dietary-induced metabolic disturbances in hyperlipidemic mice,” Phytomedicine, vol. 18, no. 5, pp. 414–424, 2011. View at Publisher · View at Google Scholar · View at Scopus
  121. J. Joven, A. Rull, E. Rodríguez-Gallego et al., “Multifunctional targets of dietary polyphenols in disease: a case for the chemokine network and energy metabolism,” Food and Chemical Toxicology, vol. 51, pp. 267–279, 2013. View at Publisher · View at Google Scholar
  122. J. Joven, E. Espinel, A. Rull et al., “Plant-derived polyphenols regulate expression of miRNA paralogs miR-103/107 and miR-122 and prevent diet-induced fatty liver disease in hyperlipidemic mice,” Biochimica et Biophysica Acta, no. 7, pp. 894–899, 1820. View at Publisher · View at Google Scholar
  123. A. Segura-Carretero, M. A. Puertas-Mejía, S. Cortacero-Ramírez et al., “Selective extraction, separation, and identification of anthocyanins from Hibiscus sabdariffa L. using solid phase extraction-capillary electrophoresis-mass spectrometry (time-of-flight/ion trap),” Electrophoresis, vol. 29, no. 13, pp. 2852–2861, 2008. View at Publisher · View at Google Scholar · View at Scopus
  124. S. C. Johnson, P. S. Rabinovitch, and M. Kaeberlein, “mTOR is a key modulator of ageing and age-related disease,” Nature, vol. 493, pp. 338–345, 2013. View at Publisher · View at Google Scholar
  125. M. Herranz-López, S. Fernández-Arroyo, A. Pérez-Sanchez et al., “Synergism of plant-derived polyphenols in adipogenesis: perspectives and implications,” Phytomedicine, vol. 19, no. 3-4, pp. 253–261, 2012. View at Publisher · View at Google Scholar
  126. S. Virtue and A. Vidal-Puig, “It's not how fat you are, it's what you do with it that counts,” PLoS Biology, vol. 6, no. 9, article e237, 2008. View at Publisher · View at Google Scholar · View at Scopus
  127. R. Singh and A. M. Cuervo, “Lipophagy: connecting autophagy and lipid metabolism,” International Journal of Cell Biology, vol. 2012, Article ID 282041, 12 pages, 2012. View at Publisher · View at Google Scholar
  128. H. J. Jansen, P. van Essen, T. Koenen, L. A. Joosten, M. G. Netea, and C. J. Tack, “Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression,” Endocrinology, vol. 153, no. 12, pp. 5866–5874, 2012. View at Publisher · View at Google Scholar