Abstract
Oxidative stress in the insulin target tissues has been implicated in the pathophysiology of type 2 diabetes. The study has examined the oxidative stress parameters in the mitochondria of subcutaneous white adipose tissue from obese and non-obese subjects with or without type 2 diabetes. An accumulation of protein carbonyls, fluorescent lipid peroxidation products, and malondialdehyde occurs in the adipose tissue mitochondria of obese type 2 diabetic, non-diabetic obese, and non-obese diabetic subjects with the maximum increase noticed in the obese type 2 diabetes patients and the minimum in non-obese type 2 diabetics. The mitochondria from obese type 2 diabetics, non-diabetic obese, and non-obese type 2 diabetics also produce significantly more reactive oxygen species (ROS) in vitro compared to those of controls, and apparently the mitochondrial ROS production rate in each group is proportional to the respective load of oxidative damage markers. Likewise, the mitochondrial antioxidant enzymes like superoxide dismutase and glutathione peroxidase show decreased activities most markedly in obese type 2 diabetes subjects and to a lesser degree in non-obese type 2 diabetes or non-diabetic obese subjects in comparison to control. The results imply that mitochondrial dysfunction with enhanced ROS production may contribute to the metabolic abnormality of adipose tissue in obesity and diabetes.
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References
West IC (2000) Radicals and oxidative stress in diabetes. Diabet Med 17:171–180
Vincent HK, Taylor AG (2006) Biomarkers and potential mechanisms of obesity induced oxidant stress in humans. Int J Obes (Lond) 30:400–418
Niemann B, Chen Y, Teschner M, Li L, Silber RE, Rohrbach S (2011) Obesity induces signs of premature cardiac aging in younger patients: the role of mitochondria. J Am Coll Cardiol 57:577–585
Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070
Kaneto H, Katakami N, Matsuhisa M, Matsuoka TA (2010) Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm 2010:453892
Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE (2005) The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem 280:4617–4626
Robertson RP, Harmon J, Tran PO, Poitout V (2004) Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53(Suppl 1):S119–S124
Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761
Gurzov EN, Tran M, Fernandez-Rojo MA, Merry TL, Zhang X, Xu Y, Fukushima A, Waters MJ, Watt MJ, Andrikopoulos S, Neel BG, Tiganis T (2014) Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2. Cell Metab 20:85–102
Paneni F, Beckman JA, Creager MA, Cosentino F (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34:2436–2443
Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625
Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194:7–15
Chakrabarti S, Sinha M, Thakurta IG, Banerjee P, Chattopadhyay M (2013) Oxidative stress and amyloid beta toxicity in Alzheimer’s disease: intervention in a complex relationship by antioxidants. Curr Med Chem 20:4648–4664
Newsholme P, Haber EP, Hirabara SM, Rebelato EL, Procopio J, Morgan D, Oliveira-Emilio HC, Carpinelli AR, Curi R (2007) Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. J Physiol 583:9–24
Sivitz WI, Yorek MA (2010) Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 12:537–577
Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13
Fato R, Bergamini C, Bortolus M, Maniero AL, Leoni S, Ohnishi T, Lenaz G (2009) Differential effects of mitochondrial Complex I inhibitors on production of reactive oxygen species. Biochim Biophys Acta 1787:384–392
Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031
Cheng Z, Almeida FA (2014) Mitochondrial alteration in type 2 diabetes and obesity: an epigenetic link. Cell Cycle 13:890–897
Sivitz WI (2010) Mitochondrial dysfunction in obesity and diabetes. US Endocrinol 6:20–27
Chattopadhyay M, Thakurta IG, Behera P, Ranjan KR, Khanna M, Mukhopadhyay S, Chakrabarti S (2011) Mitochondrial bioenergetics is not impaired in non-obese subjects with type 2 diabetes mellitus. Metabolism 60:1702–1710
Mohan V, Farooq S, Deepa M, Ravikumar R, Pitchumoni CS (2009) Prevalence of non-alcoholic fatty liver disease in urban south Indians in relation to different grades of glucose intolerance and metabolic syndrome. Diabetes Res Clin Pract 84:84–91
Kumar S, Mukherjee S, Mukhopadhyay P, Pandit K, Raychaudhuri M, Sengupta N, Ghosh S, Sarkar S, Mukherjee S, Chowdhury S (2008) Prevalance of diabetes and impaired fasting glucose in a selected population with special reference to influence of family history and anthropometric measurements—the Kolkata policeman study. J Assoc Physicians India 56:841–844
Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, Bagh MB (2011) Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxidant supplementation. Aging Dis 2:242–256
Piantadosi CA, Suliman HB (2006) Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1. J Biol Chem 281:324–333
WHO/IOTF/IASO (2000) The Asia-Pacific perspective: redefining obesity and its treatment. World Health Organization, International Obesity Task Force, International Association for the Study of Obesity, Hong Kong
Mohanty JG, Jaffe JS, Schulman ES, Raible DG (1997) A highly sensitive fluorescent micro-assay of H2O2 release from activated human leukocytes using a dihydroxy phenoxazine derivative. J Immunol Methods 202:133–141
Levine RL, Williams JA, Stadtman ER, Shacter E (1994) Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 233:346–357
Shimasaki H (1994) Assay of fluorescent lipid peroxidation products. Methods Enzymol 233:338–340
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Sun M, Zigman S (1978) An improved spectrophotometric assay for superoxide dismutase based on epinephrine autoxidation. Anal Biochem 90:81–89
Bagh MB, Thakurta IG, Biswas M, Behera P, Chakrabarti S (2011) Age-related oxidative decline of mitochondrial functions in rat brain is prevented by long term oral antioxidant supplementation. Biogerontology 12:119–131
Wendel A (1980) Glutathione peroxidase. In: Jacoby WD (ed) Enzymatic basis of detoxification, 3rd edn. Academic Press, New York, pp 333–353
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Pieczenik SR, Neustadt J (2007) Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 83:84–92
Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19
Ma ZA, Zhao Z, Turk J (2012) Mitochondrial dysfunction and β-cell failure in type 2 diabetes mellitus. Exp Diabetes Res 2012:703538
Jheng HF, Tsai PJ, Guo SM, Kuo LH, Chang CS, Su IJ, Chang CR, Tsai YS (2012) Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol 32:309–319
Mogensen M, Sahlin K, Fernstrom M, Glintborg D, Vind BF, Beck-Nielsen H, Hojlund K (2007) Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56:1592–1599
Lefort N, Glancy B, Bowen B, Willis WT, Bailowitz Z, De Filippis EA, Brophy C, Meyer C, Højlund K, Yi Z, Mandarino LJ (2010) Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes 59:2444–2452
Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX, Aziz S, Johnson JI, Bugger H, Zaha VG, Abel ED (2007) Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56:2457–2466
Hayden MS, Ghosh S (2004) Signaling to NF-kB. Genes Dev 18:2195–2224
Morgan MJ, Z-g Liu (2011) Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res 21:103–115
Marinho HS, Real C, Cyrne L, Soares H, Antunes F (2014) Hydrogen peroxide sensing, signaling and regulation of transcription factors. Redox Biol 2:535–562
Siddle K (2011) Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol 47:R1–10
Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I (2009) A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 15:1082–1087
Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K (2012) Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2:799
Chevillotte E, Giralt M, Miroux B, Ricquier D, Villarroya F (2007) Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes 56:1042–1050
Acknowledgments
The study was supported by a Grant from Council of Scientific and Industrial Research (CSIR), Government of India. (No. 27(0202)/09/EMR-II, 2009-2012). We are thankful to Dr. Manoj Khanna, Cosmetic Surgeon for his generous help in providing the adipose tissue obtained by liposuction and Ms. Indrani Roy for technical help in tissue processing. We thank the West Bengal University of Health Sciences for their help and encouragement.
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Chattopadhyay, M., Khemka, V.K., Chatterjee, G. et al. Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects. Mol Cell Biochem 399, 95–103 (2015). https://doi.org/10.1007/s11010-014-2236-7
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DOI: https://doi.org/10.1007/s11010-014-2236-7