Journal of Endocrinological Investigation

, Volume 35, Issue 1, pp 28–34 | Cite as

Rosiglitazone attenuates tumor necrosis factor-α-induced protein-tyrosine phosphatase-1B production in HepG2 cells

  • J. Wu
  • L.-J. Yang
  • D.-J. ZouEmail author
Original Article


Tumor necrosis factor (TNF)-α impairs insulin signaling and plays an important role in the development of insulin resistance. The underlying molecular mechanism by which TNF-α regulates hepatic protein-tyrosine phosphatase (PTP)-1B expression is not well understood. Rosiglitazone is used as a drug to improve insulin sensitivity in vivo. However, its effect on TNF-α-induced PTP-1B expression remains to be explored. In the present study, we sought to identify the mechanism of TNF-α-regulated hepatic PTP-1B expression and evaluate the effect of rosiglitazone on TNF-α-induced hepatic PTP-1B upregulation. TNF-α up-regulates PTP-1B expression in a dose-dependent manner and decreases insulin-stimulated phosphorylation of IR and insulin receptor substrate-1 in HepG2 cells. TNF-α increases p65 protein level and nuclear factor κB (NF-κB) activity. Inhibition of NF-κB activation by pyrrolidine dithiocarbamate impairs TNF-α-induced PTP-1B upregulation. Rosiglitazone significantly blocks TNF-α-induced PTP-1B upregulation and NF-κB activation. Our data strongly suggest that TNF-α-induced PTP-1B over-expression may contribute to hepatic IR in obesity and diabetes, and NF-κB is involved in rosiglitazone attenuated PTP-1B upregulation by TNF-α.


NF-κB PTP-1B rosiglitazone TNF-α 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 2003, 112: 1785–8.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001, 60: 349–56.PubMedCrossRefGoogle Scholar
  3. 3.
    Hotamisligil GS. Mechanisms of TNF-alpha-induced insulin resistance. Exp Clin Endocrinol Diabetes 1999, 107: 119–25.PubMedCrossRefGoogle Scholar
  4. 4.
    Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A 1994, 91: 4854–8.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Liu LS, Spelleken M, Röhrig K, Hauner H, Eckel J. Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. Diabetes 1998, 47: 515–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Ruan H, Miles PD, Ladd CM, et al. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes 2002, 51: 3176–88.PubMedCrossRefGoogle Scholar
  7. 7.
    Nieto-Vazquez I, Fernandez-Veledo S, de Alvaro C, Rondinone CM, Valverde AM, Lorenzo M. Protein-tyrosine phosphatase 1B-deficient myocytes show increased insulin sensitivity and protection against tumor necrosis factor-alpha-induced insulin resistance. Diabetes 2007, 56: 404–13.PubMedCrossRefGoogle Scholar
  8. 8.
    Seely BL, Staubs PA, Reichart DR, et al. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes 1996, 45: 1379–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Goldstein BJ, Bittner-Kowalczyk A, White MF, Harbeck M. Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. J Biol Chem 2000, 275: 4283–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Ahmad F, Azevedo JL, Cortright R, Dohm GL, Goldstein BJ. Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes. J Clin Invest 1997, 100: 449–58.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Wu X, Hoffstedt J, Deeb W, et al. Depot-specific variation in protein-tyrosine phosphatase activities in human omental and subcutaneous adipose tissue: a potential contribution to differential insulin sensitivity. J Clin Endocrinol Metab 2001, 86: 5973–80.PubMedCrossRefGoogle Scholar
  12. 12.
    Gum RJ, Gaede LL, Koterski SL, et al. Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. Diabetes 2003, 52: 21–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Zinker BA, Rondinone CM, Trevillyan JM, et al. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci U S A 2002, 99: 11357–62.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Clampit JE, Meuth JL, Smith HT, et al. Reduction of protein-tyrosine phosphatase-1B increases insulin signaling in FAO hepatoma cells. Biochem Biophys Res Commun 2003, 300: 261–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Stumvoll M. Thiazolidinediones — some recent developments. Expert Opin Investig Drugs 2003, 12: 1179–87.PubMedCrossRefGoogle Scholar
  16. 16.
    Iwata M, Haruta T, Usui I, et al. Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator—activated receptor-gamma. Diabetes 2001, 50: 1083–92.PubMedCrossRefGoogle Scholar
  17. 17.
    Jiang G, Dallas-Yang Q, Li Z, et al. Potentiation of insulin signaling in tissues of Zucker obese rats after acute and long-term treatment with PPARgamma agonists. Diabetes 2002, 51: 2412–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Hernandez R, Teruel T, Lorenzo M. Rosiglitazone produces insulin sensitisation by increasing expression of the insulin receptor and its tyrosine kinase activity in brown adipocytes. Diabetologia 2003, 46: 1618–28.PubMedCrossRefGoogle Scholar
  19. 19.
    Carpentier A, Taghibiglou C, Leung N, et al. Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem 2002, 277: 28795–802.PubMedCrossRefGoogle Scholar
  20. 20.
    Wiener JR, Kassim SK, Yu Y, Mills GB, Bast RC Jr. Transfection of human ovarian cancer cells with the HER-2/neu receptor tyrosine kinase induces a selective increase in PTP-H1, PTP-1B, PTP-alpha expression. Gynecol Oncol 1996, 61: 233–40.PubMedCrossRefGoogle Scholar
  21. 21.
    Kenner KA, Anyanwu E, Olefsky JM, Kusari J. Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem 1996, 271: 19810–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Calera MR, Vallega G, Pilch PF. Dynamics of protein-tyrosine phosphatases in rat adipocytes. J Biol Chem 2000, 275: 6308–12.PubMedCrossRefGoogle Scholar
  23. 23.
    Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 2006, 49: 434–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Chung JH, Seo AY, Chung SW, et al. Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Res Rev 2008, 7: 126–36.PubMedCrossRefGoogle Scholar
  25. 25.
    Kennedy BP, Ramachandran C. Protein tyrosine phosphatase-1B in diabetes. Biochem Pharmacol 2000, 60: 877–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005, 115: 1111–9.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin Biochem 2009, 42: 1331–46.PubMedCrossRefGoogle Scholar
  28. 28.
    Qiu W, Avramoglu RK, Dube N, et al. Hepatic PTP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins: evidence from protein tyrosine phosphatase-1B overexpression, knockout, and RNAi studies. Diabetes 2004, 53: 3057–66.PubMedCrossRefGoogle Scholar
  29. 29.
    Sun X, Han R, Wang Z, Chen Y. Regulation of adiponectin receptors in hepatocytes by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Diabetologia 2006, 49: 1303–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Lorenzo M, Fernandez-Veledo S, Vila-Bedmar R, Garcia-Guerra L, De Alvaro C, Nieto-Vazquez I. Insulin resistance induced by tumor necrosis factor-alpha in myocytes and brown adipocytes. J Anim Sci 2008, 86: E94–104.PubMedCrossRefGoogle Scholar
  31. 31.
    Delibegovic M, Zimmer D, Kauffman C, et al. Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. Diabetes 2009, 58: 590–9.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A. Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 1993, 268: 26055–8.PubMedGoogle Scholar
  33. 33.
    Ozes ON, Akca H, Mayo LD, et al. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci U S A 2001, 98: 4640–5.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Nieto-Vazquez I, Fernández-Veledo S, Krämer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M. Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem 2008, 114: 183–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Pirola L, Johnston AM, Van Obberghen E. Modulation of insulin action. Diabetologia 2004, 47: 170–84.PubMedCrossRefGoogle Scholar
  36. 36.
    Zabolotny JM, Kim YB, Welsh LA, Kershaw EE, Neel BG, Kahn BB. Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem 2008, 283: 14230–41.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994, 331: 1188–93.PubMedCrossRefGoogle Scholar
  38. 38.
    Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996, 45: 1661–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Hernandez R, Teruel T, de Alvaro C, Lorenzo M. Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-alpha induction of p38 and p42/p44 mitogen-activated protein kinases. Diabetologia 2004, 47: 1615–24.PubMedCrossRefGoogle Scholar
  40. 40.
    Cohen SE, Tseng YH, Michael MD, Kahn CR. Effects of insulin-sensitising agents in mice with hepatic insulin resistance. Diabetologia 2004, 47: 407–11.PubMedCrossRefGoogle Scholar
  41. 41.
    Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 2002, 51: 1319–36.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2012

Authors and Affiliations

  1. 1.Department of Endocrinology, Changhai HospitalThe Second Military Medical UniversityShanghaiChina
  2. 2.Department of Oncology, Chang Hai Hospitalthe Second Military Medical UniversityShanghaiPR China

Personalised recommendations