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Accelerated fat cell aging links oxidative stress and insulin resistance in adipocytes

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Abstract

Telomere shortening is emerging as a biological indicator of accelerated aging and aging-related diseases including type 2 diabetes. While telomere length measurements were largely done in white blood cells, there is lack of studies on telomere length in relation to oxidative stress in target tissues affected in diabetes. Therefore, the aim of this study is to induct oxidative stress in adipocytes and to test whether these adipocytes exhibit shortened telomeres, senescence and functional impairment. 3T3-L1 adipocytes were subjected to oxidative stress and senescence induction by a variety of means for 2 weeks (exogenous application of H2O2, glucose oxidase, asymmetric dimethylarginine (ADMA) and glucose oscillations). Cells were probed for reactive oxygen species generation (ROS), DNA damage, mRNA and protein expression of senescent and pro-inflammatory markers, telomere length and glucose uptake. Compared to untreated cells, both ROS generation and DNA damage were significantly higher in cells subjected to oxidative stress and senescence. Adipocytes subjected to oxidative stress also showed shortened telomeres and increased mRNA and protein expression of p53, p21, TNFα and IL-6. Senescent cells were also characterized by decreased levels of adiponectin and impaired glucose uptake. Briefly, adipocytes under oxidative stress exhibited increased ROS generation, DNA damage, shortened telomeres and switched to senescent/pro-inflammatory phenotype with impaired glucose uptake.

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Abbreviations

ADMA:

asymmetric

NG :

NG-dimethylarginine

FBS:

fetal bovine serum

GO:

glucose oxidase

H2O2 :

hydrogen peroxide

IBMX:

iso-butyl methyl xanthine

ROS:

reactive oxygen species

SA-β-gal:

senescence-associated β-galactosidase

References

  • Adaikalakoteswari A, Balasubramanyam M and Mohan V 2005 Telomere shortening occurs in Asian Indian Type 2 diabetic patients. Diab. Med. 22 1151–1156

    Article  CAS  Google Scholar 

  • Adaikalakoteswari A, Rema M, Mohan V and Balasubramanyam M 2007 Oxidative DNA damage and augmentation of poly(ADP-ribose) polymerase/nuclear factor-kappa B signaling in patients with type 2 diabetes and microangiopathy. Int. J. Biochem. Cell Biol. 39 1673–1684

    Article  PubMed  CAS  Google Scholar 

  • Adelibieke Y, Shimizu H, Muteliefu G, Bolati D and Niwa T 2012 Indoxyl sulfate induces endothelial cell senescence by increasing reactive oxygen species production and p53 activity. J. Ren. Nutr. 22 86–89

    Article  PubMed  CAS  Google Scholar 

  • Ahima RS 2009 Connecting obesity, aging and diabetes. Nat. Med. 15 996–997

    Article  PubMed  CAS  Google Scholar 

  • Arai Y, Takayama M, Abe Y and Hirose N 2011 Adipokines and aging. J. Atheroscler. Thromb. 18 545–550

    Article  PubMed  CAS  Google Scholar 

  • Balasubramanyam M, Adaikalakoteswari A, Monickaraj SF and Mohan V 2007 Telomere shortening & metabolic/vascular diseases. Indian J. Med. Res. 125 441–450

    PubMed  CAS  Google Scholar 

  • Balasubramanyam M, Aravind S, Gokulakrishnan K, Prabu P, Sathishkumar C, Ranjani H and Mohan V 2011 Impaired miR-146a expression links subclinical inflammation and insulin resistance in Type 2 diabetes. Mol. Cell Biochem. 351 197–205

    Article  PubMed  CAS  Google Scholar 

  • Beliveau A and Yaswen P 2007 Soothing the watchman: telomerase reduces the p53-dependent cellular stress response. Cell Cycle 6 1284–1287

    Article  PubMed  CAS  Google Scholar 

  • Bode-Böger SM, Scalera F and Martens-Lobenhoffer J 2005 Asymmetric dimethylarginine (ADMA) accelerates cell senescence. Vasc. Med. 10 (Suppl 1) S65–S71

    Article  PubMed  Google Scholar 

  • Burgdorf KS, Grarup N, Justesen JM, Harder MN, Witte DR, Jørgensen T, Sandbæk A, Lauritzen T, et al. 2011 Studies of the association of Arg72Pro of tumor suppressor protein p53 with type 2 diabetes in a combined analysis of 55,521 Europeans. PLoS One 6 e15813

    Article  PubMed  CAS  Google Scholar 

  • Campisi J 2005 Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120 513–522

    Article  PubMed  CAS  Google Scholar 

  • Cawthon RM 2002 Telomere measurement by quantitative PCR. Nucleic Acids Res. 30 e47

    Article  PubMed  Google Scholar 

  • Chang J, Li Y, Huang Y, Lam KS, Hoo RL, Wong WT, Cheng KK, Wang Y, et al. 2010 Adiponectin prevents diabetic premature senescence of endothelial progenitor cells and promotes endothelial repair by suppressing the p38 MAP kinase/p16INK4A signaling pathway. Diabetes 259 2949–2959

    Article  Google Scholar 

  • Guarner-Lans V, Rubio-Ruiz ME, Pérez-Torres I and Baños de MacCarthy G 2011 Relation of aging and sex hormones to metabolic syndrome and cardiovascular disease. Exp. Gerontol. 46 517–523

    Article  PubMed  CAS  Google Scholar 

  • Herbig U, Jobling WA, Chen BP, Chen DJ and Sedivy JM 2004 Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell. 14 501–513

    Article  PubMed  CAS  Google Scholar 

  • Hotamisligil GS, Shargill NS and Spiegelman BM 1993 Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259 87–91

    Article  PubMed  CAS  Google Scholar 

  • Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, et al. 2006 Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J. Biol. Chem. 281 26602–26614

    Article  PubMed  CAS  Google Scholar 

  • Lu T and Finkel T 2008 Free radicals and senescence. Exp. Cell Res. 314 1918–1922

    Article  PubMed  CAS  Google Scholar 

  • Meazza C, Vitale G, Pagani S, Castaldi D, Ogliari G, Mari D, Laarej K, Tinelli C, et al. 2011 Common adipokine features of neonates and centenarians. J. Pediatr. Endocrinol. Metab. 24 953–957

    Article  PubMed  Google Scholar 

  • Mehta JL, Rasouli N, Sinha AK and Molavi B 2006 Oxidative stress in diabetes: A mechanistic overview of its effects on atherogenesis and myocardial dysfunction. Int. J. Biochem. Cell Biol. 38 794–803

    Article  PubMed  CAS  Google Scholar 

  • Minamino T and Komuro I 2007 Vascular cell senescence: contribution to atherosclerosis. Circ. Res. 100 15–26

    Article  PubMed  CAS  Google Scholar 

  • Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, et al. 2009 A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15 1082–1087

    Article  PubMed  CAS  Google Scholar 

  • Monickaraj F, Aravind S, Gokulakrishnan K, Sathishkumar C, Prabu P, Prabu D, Mohan V and Balasubramanyam M 2012 Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes. Mol. Cell Biochem. 365 343–350

    Article  PubMed  CAS  Google Scholar 

  • Morley JE, 2008 Diabetes and aging: epidemiologic overview. Clin. Geriatr. Med. 24 395–405

    Article  PubMed  Google Scholar 

  • Otabe S, Wada N, Hashinaga T, Yuan X, Shimokawa I, Fukutani T, Tanaka K, Ohki T, et al. 2012 Hyperadiponectinemia protects against premature death in metabolic syndrome model mice by inhibiting Akt signaling and chronic inflammation. J. Endocrinol. 213 67–76

    Article  PubMed  CAS  Google Scholar 

  • Otabe S, Yuan X, Fukutani T, Wada N, Hashinaga T, Nakayama H, Hirota N, Kojima M, et al. 2007 Overexpression of human adiponectin in transgenic mice results in suppression of fat accumulation and prevention of premature death by high-calorie diet. Am. J. Physiol. Endocrinol. Metab. 293 E210–E218

    Article  PubMed  CAS  Google Scholar 

  • Qu L, He B, Pan Y, Xu Y, Zhu C, Tang Z, Bao Q, Tian F, et al. 2011 Association between polymorphisms in RAPGEF1, TP53, NRF1 and type 2 diabetes in Chinese Han population. Diabetes Res. Clin. Pract. 91 171–176

    Article  PubMed  CAS  Google Scholar 

  • Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu IH, Chen K, Yamamoto-Hiraoka J, et al. 2010 Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab. 11 379–389

    Article  PubMed  CAS  Google Scholar 

  • Salpea KD, Talmud PJ, Cooper JA, Maubaret CG, Stephens JW, Abelak K and Humphries SE 2010 Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis 209 42–50

    Article  PubMed  CAS  Google Scholar 

  • Sampson MJ, Winterbone MS, Hughes JC, Dozio N and Hughes DA 2006 Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diab. Care. 29 283–289

    Article  CAS  Google Scholar 

  • Schisano B, Tripathi G, McGee K, McTernan PG and Ceriello A 2011 Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. Diabetologia 54 1219–1226

    Article  PubMed  CAS  Google Scholar 

  • Shimizu I, Yoshida Y, Katsuno T, Tateno K, Okada S, Moriya J, Yokoyama M, Nojima A, et al. 2012 p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. Cell Metab. 15 51–64

    Google Scholar 

  • Singh NP, McCoy MT, Tice RR and Schneider EL 1988 A simple technique for quantitation of low levels of DNA damage in individual cells. Exp. Cell Res. 175 184–191

    Article  PubMed  CAS  Google Scholar 

  • Sydow K, Mondon CE, Schrader J, Konishi H and Cooke JP 2008 Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity. Arterioscler. Thromb. Vasc. Biol. 28 692–697

    Article  PubMed  CAS  Google Scholar 

  • Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, et al. 2010 Fat tissue, aging, and cellular senescence. Aging Cell 9 667–684

    Article  PubMed  CAS  Google Scholar 

  • Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL and Ferrante AW Jr 2003 Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112 1796–1808

    PubMed  CAS  Google Scholar 

  • Yang ZC, Wang KS, Wu Y, Zou XQ, Xiang YY, Chen XP and Li YJ 2009 Asymmetric dimethylarginine impairs glucose utilization via ROS/TLR4 pathway in adipocytes: an effect prevented by vitamin E. Cell Physiol. Biochem. 24 115–124

    Article  PubMed  Google Scholar 

  • Yi L, Zhang P, Ji X, Liang Y, Wang Y, Zhou Z and Chen B 2011 Quantitation of L-arginine and asymmetric dimethylarginine in human plasma by LC-selective ion mode-MS for Type 2 diabetes mellitus study. Chem. Pharm. Bull. (Tokyo) 59 839–843

    Article  CAS  Google Scholar 

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Acknowledgements

The present work was supported by a grant from the Department of Biotechnology (DBT), India. Financial assistance through Senior Research Fellowship by the Council of Scientific and Industrial Research (CSIR), India, is also acknowledged.

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Authors and Affiliations

  1. Madras Diabetes Research Foundation and Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-Communicable Diseases Prevention and Control, IDF Centre of Education, Gopalapuram, Chennai, 600 086, India

    Finny Monickaraj, Sankaramoorthy Aravind, Pichamoorthy Nandhini, Paramasivam Prabu, Chandrakumar Sathishkumar, Viswanathan Mohan & Muthuswamy Balasubramanyam

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  1. Finny Monickaraj
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  2. Sankaramoorthy Aravind
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  3. Pichamoorthy Nandhini
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  4. Paramasivam Prabu
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  5. Chandrakumar Sathishkumar
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  6. Viswanathan Mohan
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  7. Muthuswamy Balasubramanyam
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Corresponding author

Correspondence to Muthuswamy Balasubramanyam.

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Corresponding editor: VEENA K PARNAIK

[Monickaraj F, Aravind S, Nandhini P, Prabu P, Sathishkumar C, Mohan V and Balasubramanyam M 2013 Accelerated fat cell aging links oxidative stress and insulin resistance in adipocytes. J. Biosci. 38 1–10] DOI 10.1007/s12038-012-9289-0

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Monickaraj, F., Aravind, S., Nandhini, P. et al. Accelerated fat cell aging links oxidative stress and insulin resistance in adipocytes. J Biosci 38, 113–122 (2013). https://doi.org/10.1007/s12038-012-9289-0

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