Molecular and Cellular Biochemistry

, Volume 182, Issue 1–2, pp 169–175

TNF-α and insulin resistance: Summary and future prospects

  • Pascal Peraldi
  • Bruce Spiegelman


While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-α) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-a in insulin resistance during obesity and how TNF-α interferes with insulin signaling.

insulin resistance TNF-α obesity insulin signaling adipocyte IRS-1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sigal RJ, Warram JH: The interaction between obesity and diabetes. Curr Opin Endocrinol Diab 3: 3–9, 1996Google Scholar
  2. 2.
    Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Dernick R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV: Human tumor necrosis factor: Precursor structure, expression and homology to lymphotoxin. Nature 312: 724–727, 1984PubMedGoogle Scholar
  3. 3.
    Gray PW, Aggarwal BB, Benton CV, Bringman TS, Henzel WJ, Jarret JA, Leung DW, Moffat BNP, Svedersky LP, Palladino MA, Nedwin GE: Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis activity. Nature 312: 721–724, 1984PubMedGoogle Scholar
  4. 4.
    Fiers W: Tumor necrosis factor. FEBS Lett 285: 199–212, 1991PubMedGoogle Scholar
  5. 5.
    Vassalli P: The pathophysiology of tumor necrosis factors. Annu Rev Immunol 10: 411–452, 1992PubMedGoogle Scholar
  6. 6.
    Tracey KJ, Cerami A: Tumor necrosis factor, and other cytokines and disease. Annu Rev Cell Biol 9: 317–343, 1993PubMedGoogle Scholar
  7. 7.
    Vandenabeele P, Declercq W, Beyaert R, Fiers W: Two tumor necrosis factor receptors: Structure and function. Trends Cell Biol 5: 392–399, 1995PubMedGoogle Scholar
  8. 8.
    Kriegler M, Perez C, DeFay K, Albert I, Lu S: A novel form of TNF/ cachectin is a cell surface cytotoxic transmembrane protein: Ramifications for the complex physiology of TNF. Cell 53: 45–53, 1988PubMedGoogle Scholar
  9. 9.
    Mohler K, Sleath P, Fitzner J, Cerretti D, Alderson M, Kerwar S, Torrance D, Otten-Evans C, Greenstreet T, Weerawarna K, Al E: Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature 370: 218–220, 1994PubMedGoogle Scholar
  10. 10.
    Gearing A, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson A, Drummond A, Galloway W, Gilbert R, Gordon J, Al E: Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature 370: 555–558, 1994PubMedGoogle Scholar
  11. 11.
    Bazzoni F, Beutler B: How do tumor necrosis factor receptors work? J Inflam 45: 221–238, 1995Google Scholar
  12. 12.
    Tartaglia LA, Weber RF, Figari IS, Reynolds C, Palladino JMA, Goeddel DV: The two different receptors for tumor necrosis factor mediates distinct cellular responses. Proc Natl Acad Sci USA 88: 9292–9296, 1991PubMedGoogle Scholar
  13. 13.
    Tartaglia L, Pennica P, Goeddel D: Ligand passing: The 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor. J Biol Chem 268: 18542–18548, 1993PubMedGoogle Scholar
  14. 14.
    Rothe M, Wong SC, Henzel WJ, Goeddel DV: A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78: 681–692, 1994PubMedGoogle Scholar
  15. 15.
    Rothe M, Pan M, Henzel W, Ayres T, Goeddel D: The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83: 1243–1252, 1995PubMedGoogle Scholar
  16. 16.
    Rothe M, Xiong J, Shu H-B, Williamson K, Goddard A, Goeddel DV: ITRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction. Proc Natl Acad Sci USA 93: 8241–8246, 1996PubMedGoogle Scholar
  17. 17.
    Adam-Klages S, Adam D, Wiegman K, Struve S, Kolanus W, Schneider-Mergener J, Kronke M: FAN, a novel WD-repeat protein, couples the p55TNF-receptor to neutral sphingomyelinase. Cell 86: 937–947, 1996PubMedGoogle Scholar
  18. 18.
    Hsu H, Xiong J, Goeddel D: The TNF receptor 1-associated protein TRADD signals death and NF-κB activation. Cell 81: 495–504, 1995PubMedGoogle Scholar
  19. 19.
    Hsu H, Shu HB, Pan MG, Goeddel DV: TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signaling transduction pathways. Cell 84: 299–308, 1996PubMedGoogle Scholar
  20. 20.
    Stanger B, Leder P, Lee T, Kim E, Seed B: RIP: A novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell 81: 513–523, 1995PubMedGoogle Scholar
  21. 21.
    Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV: TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4: 387–396, 1996PubMedGoogle Scholar
  22. 22.
    Boldin MP, Goncharov TM, Goltsev YV, Wallach D: Involvement of MACH, a novel MORT1/FADD-interacting protease, in FAS/APO-1 and TNF receptor induced cell death. Cell 85: 803–815, 1996PubMedGoogle Scholar
  23. 23.
    Muzio M, Chinnaiyan A, Kischkel F, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz J, Zhang M, Gentz R, Mann M, Krammer P, Peter M, Dixit V: FLICK, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85: 817–827, 1996PubMedGoogle Scholar
  24. 24.
    Wang C-Y, Mayo MW, Baldwin AS: TNF-and cancer therapy-induced apoptosis: potential by inhibition of NF-κB. Science 274: 784–786, 1996PubMedGoogle Scholar
  25. 25.
    Beg AA, Baltimore D: An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274: 782–784, 1996PubMedGoogle Scholar
  26. 26.
    Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM: Supression of TNFα-induced apoptosis by NF-κb. Science 274: 787–789, 1996PubMedGoogle Scholar
  27. 27.
    Liu Z-g, Hsu H, Goeddel DV, Karin M: Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87: 565–576, 1996PubMedGoogle Scholar
  28. 28.
    Van Dongen CJ, Zwiers H, Gispen WH: Purification and partial characterization of the phosphatidylinositol 4-phosphate kinase from rat brain. Biochem J 223: 197–203, 1984PubMedGoogle Scholar
  29. 29.
    Lang CH, Dobrescu C, Bagby GJ: Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130: 43–52, 1992PubMedGoogle Scholar
  30. 30.
    Grunfeld C, Feingold K: The metabolic effect of tumor necrosis factor and other cytokines. Biotherapy 3: 143–158, 1991PubMedGoogle Scholar
  31. 31.
    Torti FM, Dieckmann B, Beutler B, Cerami A, Ringold GM: A macrophage factor inhibits adipocyte gene expression: An in vitro model for cachexia. Science 229: 867–869, 1985PubMedGoogle Scholar
  32. 32.
    Grunfeld C, Feingold K: Metabolic disturbance and wasting in the acquired immunodeficiency syndrome. N Engl J Med 327: 329–337, 1992PubMedGoogle Scholar
  33. 33.
    Copeland GP, Leinster SJ, Davis JC, Hipkin LJ: Insulin resistance in patient with colorectal cancer. Br J Surg 74: 1031–1035, 1987PubMedGoogle Scholar
  34. 34.
    Marano M, Moldawer L, Fong Y, Al E: cachectin/TNF production in experimental burns and pseudonomas infection. Arch Surg 123: 1383–1388, 1988PubMedGoogle Scholar
  35. 35.
    Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science 259: 87–91, 1993PubMedGoogle Scholar
  36. 36.
    Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ, Hotamisligil GS, Spiegelman BM: Altered gene expression for tumor necrosis factor-α and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 134: 264–270, 1994PubMedGoogle Scholar
  37. 37.
    Lowell BB, Susulic S, Hamann A, Lawitts JA, Himms H-J, Boyer BB, Kozak LP, Flyers JS: Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366: 740–742, 1993PubMedGoogle Scholar
  38. 38.
    Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 95: 2409–2415, 1995PubMedGoogle Scholar
  39. 39.
    Kern P, Saghizadeh M, Ong J, Bosch R, Deem R, Simsolo R: The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95: 2111–2119, 1995PubMedGoogle Scholar
  40. 40.
    Saghizadeh M, Ong JM, Garvey TW, Henry R, Kern PA: The expression of TNF-α by human muscle. J Clin Invest 97: 1111–1116, 1996PubMedGoogle Scholar
  41. 41.
    Hotamisligil GS, Budavari A, Murray D, Spiegelman BM: Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. J Clin Invest 94: 1543–1549, 1994PubMedGoogle Scholar
  42. 42.
    Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM: Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274: 1377–1379, 1996PubMedGoogle Scholar
  43. 43.
    Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM: Tumor necrosis factor α inhibits signaling from the insulin receptor. Proc Natl Acad Sci 91: 4854–4858, 1994PubMedGoogle Scholar
  44. 44.
    Stephens J, Pekala P: Transcriptional repression of the C/EBP-alpha and GLUT4 genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. Regulations is coordinate and independent of protein synthesis. J Biol Chem 267: 13580–13584, 1992PubMedGoogle Scholar
  45. 45.
    Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A: Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 268: 26055–26058, 1993PubMedGoogle Scholar
  46. 46.
    Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM: Tumor necrosis factor (TNF)-α inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J Biol Chem 271: 13018–13022, 1996PubMedGoogle Scholar
  47. 47.
    Kroder G, Bossenmayer B, Kellerer M, Capp E, Stoyanov B, Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H: Tumor necrosis factor α and hyperglycemia-induced insulin resistance. J Clin Invest 97: 1471–1477, 1996PubMedGoogle Scholar
  48. 48.
    White MF, Kahn CR: The insulin signaling system. J Biol Chem 269: 1–4, 1994PubMedGoogle Scholar
  49. 49.
    Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α-and obesity-induced insulin resistance. Science 271: 665–668, 1996PubMedGoogle Scholar
  50. 50.
    Kanety H, Feinstein R, Papa M, Hemi R, Karasik A: Tumor necrosis factor-α-induced phosphorylation of insulin receptor substrate-1 (IRS-1). J Biol Chem 270: 23780–23784, 1995PubMedGoogle Scholar
  51. 51.
    Kolesnick R, Golde D: The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 77: 325–328, 1994PubMedGoogle Scholar
  52. 52.
    Lozano J, Berra E, Municio M, Diaz-Meco M, Dominguez I, Sanz L, Moscat J: Protein kinase C isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. J Biol Chem 269: 19200–19202, 1994PubMedGoogle Scholar
  53. 53.
    Muller G, Ayoub M, Storz P, Rennecke J, Fabbro D, Pfizenmaier K: PKC ζ is a molecular switch in signal transduction of TNF-α bifunctionally regulated by ceramide and arachidonic acid. EMBO J 14: 1156–1165, 1995PubMedGoogle Scholar
  54. 54.
    Yao B, Zhang Y, Delikat S, Mathias S, Basu S, Kolesnick R: Phosphorylation of Raf by ceramide-activated protein kinase. Nature 378: 307–310, 1995PubMedGoogle Scholar
  55. 55.
    Dobrowsky R, Hannun Y: Ceramide stimulates a cytosolic protein phosphatase. J Biol Chem 267: 5048–5051, 1992PubMedGoogle Scholar
  56. 56.
    Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R: Effects of an engineered human anti-TNF-α antibody (CPD571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45: 881–885, 1996PubMedGoogle Scholar
  57. 57.
    Boden G, Chen X, Ruiz J, White JV, Rosseti L: Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93: 2438–2446, 1994PubMedGoogle Scholar
  58. 58.
    Muller HK, Kellerer B, Ermel A, Muhlhofer B, Obermaier-Kusser B, Vogt B, Haring HC: Prevention by protein kinase C inhibitors of glucose-induced insulin receptor tyrosine kinase resistance in rat fat cells. Diabetes 40: 1440–1448, 1991PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Pascal Peraldi
    • 1
  • Bruce Spiegelman
    • 1
  1. 1.Dana Farber Cancer InstituteHarvard Medical SchoolBostonUSA

Personalised recommendations