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Overexpression of superoxide dismutase 3 gene blocks high-fat diet-induced obesity, fatty liver and insulin resistance

Gene Therapy volume 21, pages 840–848 (2014)Cite this article

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Abstract

Oxidative stress has an important role in the development of obesity and obesity-associated metabolic disorders. As an endogenous antioxidant enzyme, superoxide dismutase 3 (SOD3) has the potential to affect diet-induced obesity and obesity-associated complications. In the current work, we overexpressed SOD3 in C57BL/6 mice fed a high-fat diet (HFD) to study its effect on HFD-induced obesity, fatty liver and insulin resistance. We demonstrated that the Sod3 gene transfer blocked HFD-induced obesity, fatty liver and insulin resistance. Real-time PCR analysis of adipose and liver tissues revealed that overexpression of the Sod3 gene suppressed expression of pro-inflammatory genes in adipose tissue including F4/80, Tnfα, Cd11c, Mcp1 and Il6, and increased expression of anti-inflammatory genes such as adiponectin. In the liver, high levels of SOD3 activity in animals enhanced expression of the genes responsible for energy expenditure including Cpt1α, Cpt1β, Pgc1α, Pgc1β and Ucp2. These results suggest that overexpression of the Sod3 gene through gene transfer is an effective approach in preventing diet-induced obesity and obesity-associated complications.

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References

  1. Matsuda M, Shimomura I . Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract 2013; 7: e330–e341.

    Article  PubMed  Google Scholar 

  2. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752–1761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yang H, Jin X, Lam K, Yan SK . Oxidative stress and diabetes mellitus. Clin Chem Lab Med 2011; 49: 1773–1782.

    CAS  PubMed  Google Scholar 

  4. Drummond GR, Selemidis S, Griendling KK, Sobey CG . Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 2011; 10: 453–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Marklund SL, Nilsson P, Israelsson K, Schampi I, Peltonen M, Asplund K . Two variants of extracellular superoxide dismutase: relationship to cardiovascular risk factors in an unselected middle‐aged population. J Intern Med 1997; 242: 5–14.

    Article  CAS  PubMed  Google Scholar 

  6. Adachi T, Inoue M, Hara H, Maehata E, Suzuki S . Relationship of plasma extracellular-superoxide dismutase level with insulin resistance in type 2 diabetic patients. J Endocrinol 2004; 181: 413–417.

    Article  CAS  PubMed  Google Scholar 

  7. Isogawa A, Yamakado M, Yano M, Shiba T . Serum superoxide dismutase activity correlates with the components of metabolic syndrome or carotid artery intima-media thickness. Diabetes Res Clin Pract 2009; 86: 213–218.

    Article  CAS  PubMed  Google Scholar 

  8. Lehmann TG, Wheeler MD, Froh M, Schwabe RF, Bunzendahl H, Samulski RJ et al. Effects of three superoxide dismutase genes delivered with an adenovirus on graft function after transplantation of fatty livers in the Rats. Transplantation 2003; 76: 28–37.

    Article  CAS  PubMed  Google Scholar 

  9. Laurila JP, Castellone MD, Curcio A, Laatikainen LE, Haaparanta-Solin M, Gronroos TJ et al. Extracellular superoxide dismutase is a growth regulatory mediator of tissue injury recovery. Mol Ther 2009; 17: 448–454.

    Article  CAS  PubMed  Google Scholar 

  10. Gottfredsen RH, Goldstrohm DA, Hartney JM, Larsen UG, Bowler RP, Petersen SV . The cellular distribution of extracellular superoxide dismutase in macrophages is altered by cellular activation but unaffected by the naturally occurring R213G substitution. Free Radic Biol Med 2014; 69: 348–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bu L, Gao M, Qu S, Liu D . Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J 2013; 15: 1001–1011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Monteiro R, Azevedo I . Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010; doi:10.1155/2010/289645.

  13. Sun K, Kusminski CM, Scherer PE . Adipose tissue remodeling and obesity. J Clin Invest 2011; 121: 2094–2101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yamaguchi N, Argueta J G M, Masuhiro Y, Kagishita M, Nonaka K, Saito T et al. Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS Lett 2005; 579: 6821–6826.

    Article  CAS  PubMed  Google Scholar 

  15. Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 2004; 109: 2046–2049.

    Article  CAS  PubMed  Google Scholar 

  16. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8: 731–737.

    Article  CAS  PubMed  Google Scholar 

  17. Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N et al. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 2010; 285: 6153–6160.

    Article  CAS  PubMed  Google Scholar 

  18. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A et al. Fat Treg cells: a liaison between the immune and metabolic systems. Nat Med 2009; 15: 930–939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guilherme A, Virbasius JV, Puri V, Czech MP . Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 2008; 9: 367–377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tamai M, Furuta H, Kawashima H, Doi A, Hamanishi T, Shimomura H et al. Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes. Diabetes Res Clin Pract 2006; 71: 140–145.

    Article  CAS  PubMed  Google Scholar 

  21. Mysore TB, Shinkel TA, Collins J, Salvaris EJ, Fisicaro N, Murray-Segal LJ et al. Overexpression of glutathione peroxidase with two isoforms of superoxide dismutase protects mouse islets from oxidative injury and improves islet graft function. Diabetes 2005; 54: 2109–2116.

    Article  CAS  PubMed  Google Scholar 

  22. Adachi T, Inoue M, Hara H, Suzuki S . Effects of PPARgamma ligands and C/EBPbeta enhancer on expression of extracellular-superoxide dismutase. Redox Rep 2004; 9: 207–212.

    Article  CAS  PubMed  Google Scholar 

  23. Madan K, Bhardwaj P, Thareja S, Gupta SD, Saraya A . Oxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD). J Clin Gastroenterol 2006; 40: 930–935.

    Article  CAS  PubMed  Google Scholar 

  24. Carmiel-Haggai M, Cederbaum AI, Nieto N . A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. FASEB J 2005; 19: 136–138.

    Article  CAS  PubMed  Google Scholar 

  25. Wheeler MD, Katuna M, Smutney OM, Froh M, Dikalova A, Mason RP et al. Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia-reperfusion injury. Hum Gene Ther 2001; 12: 2167–2177.

    Article  CAS  PubMed  Google Scholar 

  26. Bujanda L, Hijona E, Larzabal M, Beraza M, Aldazabal P, García-Urkia N et al. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol 2008; 8: 40.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Laurent A, Nicco C, Tran Van Nhieu J, Borderie D, Chéreau C, Conti F et al. Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis. Hepatology 2004; 39: 1277–1285.

    Article  CAS  PubMed  Google Scholar 

  28. Laviña B, Gracia-Sancho J, Rodríguez-Vilarrupla A, Chu Y, Heistad DD, Bosch J et al. Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension. Gut 2009; 58: 118–125.

    Article  PubMed  Google Scholar 

  29. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941–946.

    Article  CAS  PubMed  Google Scholar 

  30. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 2001; 50: 1126–1133.

    Article  CAS  PubMed  Google Scholar 

  31. Diez JJ, Iglesias P . The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003; 148: 293–300.

    Article  CAS  PubMed  Google Scholar 

  32. Menzaghi C, Trischitta V, Doria A . Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes 2007; 56: 1198–1209.

    Article  CAS  PubMed  Google Scholar 

  33. Li L, Wu L, Wang C, Liu L, Zhao Y . Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes. Regul Pept 2007; 139: 72–79.

    Article  PubMed  Google Scholar 

  34. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M et al. Adiponectin and AdipoR1 regulate PGC-1 [agr] and mitochondria by Ca2+ and AMPK/SIRT1. Nature 2010; 464: 1313–1319.

    Article  CAS  PubMed  Google Scholar 

  35. Zhou M, Xu A, Tam PK, Lam KS, Huang B, Liang Y . Upregulation of UCP2 by adiponectin: the involvement of mitochondrial superoxide and hnRNP K. PLoS One 2012; 7: e32349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu F, Song YK, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy 1999; 6: 1258–1266.

    Article  CAS  PubMed  Google Scholar 

  37. McCord JM, Fridovich I . Superoxide dismutase an enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969; 244: 6049–6055.

    CAS  PubMed  Google Scholar 

  38. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  39. Folch J, Lees M, Sloane-Stanley GH . A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957; 226: 497–509.

    CAS  PubMed  Google Scholar 

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Acknowledgements

The study was supported in part by grants from NIH (RO1EB007357 and RO1HL098295). RC is a recipient of Scholarship (No. 201306260063) from the China Scholarship Council. We would like to thank Ms Ryan Fugett for proofreading and English editing of the manuscript.

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Authors and Affiliations

  1. Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China

    R Cui & S Qu

  2. Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, GA, USA

    R Cui, M Gao & D Liu

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  1. R Cui
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Correspondence to D Liu.

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Cui, R., Gao, M., Qu, S. et al. Overexpression of superoxide dismutase 3 gene blocks high-fat diet-induced obesity, fatty liver and insulin resistance. Gene Ther 21, 840–848 (2014). https://doi.org/10.1038/gt.2014.64

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