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Horm Metab Res 2010; 42(2): 115-121
DOI: 10.1055/s-0029-1241834
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

TNF-α Inhibits Insulin Action in Liver and Adipose Tissue: A Model of Metabolic Syndrome

S. S. Solomon1 , 2 , 3 , O. Odunusi1 , 2 , D. Carrigan1 , 2 , G. Majumdar1 , 2 , D. Kakoola1 , 2 , N. I. Lenchik1 , 2 , I. C. Gerling1 , 2
  • 1Department of Medicine, University of Tennessee Health Science Center, Veterans Affairs Medical Center, Memphis, Tennessee, USA
  • 2University of Tennessee Research Service, Veterans Affairs Medical Center, Memphis, Tennessee, USA
  • 3Department of Pharmacology, University of Tennessee Health Science Center, Veterans Affairs Medical Center, Memphis, Tennessee, USA
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Publikationsverlauf

received 29.06.2009

accepted 07.10.2009

Publikationsdatum:
03. Dezember 2009 (online)

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Abstract

Several studies suggest that TNF-α contributes to the development of insulin resistance (IR). We compared transcriptional profiles of rat H-411E liver cells exposed to insulin in the absence or presence of TNF-α. We identified 33 genes whose expression was altered by insulin, and then reversed by TNF-α. Twenty-six of these 33 genes created a single network centered around: insulin, TNF-α, p38-MAPK, TGFb1; SMAD and STAT1; and enzymes and cytokines involved in apoptosis (CASP3, GADD45B, IL2, TNF-α, etc.). We analyzed our data together with other data of gene expression in adipocytes and found a number of processes common to both, for example, cell death and inflammation; intercellular signaling and metabolism; G-Protein, IL-10 and PTEN signaling. Moreover, the two datasets combined generated a single molecular network that further identified PTEN (a phosphatase) as a unique new link between insulin signaling, IR, and apoptosis reflecting the pathophysiology of “metabolic syndrome”.

Key words

metabolic syndrome model - liver cells - tissue culture - genomics - insulin - receptor and signaling - phosphorylation - energy utilization - apoptosis

References

  • 1 Eckel J, Asskamp B, Reinauer H. Induction of insulin resistance in primary cultured adult cardiamyocytes.  Endocrinology. 1991;  29 345-352
    Suche in Google Scholar
  • 2 Piccini JP, Klein L, Gheorghiade M, Bonow RO. New insights into diastolic heart failure: role of diabetes mellitus.  Am J Med. 2004;  116 ((Suppl 5A)) 645-675S
    Suche in Google Scholar
  • 3 Nesto RW. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association: Response to Elasy and Griffin.  Diabetes Care. 2004;  27 2096
    Suche in Google Scholar
  • 4 Sobel BE. Insulin resistance predicts CHF (Ed).  Clinical Insights in Diabetes. 2005;  8 2
    Suche in Google Scholar
  • 5 Ingelsson, E, Sundström J, Arnlöv J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure.  J Am Med Assoc. 2005;  294 334-341
    Suche in Google Scholar
  • 6 Duckworth WC, Solomon SS, Jallepalli P, Heckemeyer C, Finnern J, Powers AC. Glucose intolerance due to insulin resistance in patients with spinal cord injuries.  Diabetes. 1980;  29 906-910
    Suche in Google Scholar
  • 7 Shankar TP, Solomon SS, Duckworth WC, Himmelstein S, Gray S, Jerkins T, Babal MA, Ramamurthy SI. Studies of glucose intolerance in cirrhosis of the liver.  J Lab Clin Med. 1983;  102 459-469
    Suche in Google Scholar
  • 8 Shankar TP, Fredi JL, Himmelstein S, Solomon SS, Duckworth WC. Elevated growth hormone levels and insulin resistance in patients with cirrhosis of the Liver.  Am J Med Sci. 1986;  291 248-254
    Suche in Google Scholar
  • 9 Shankar TP, Solomon SS, Duckworth WC, Jerkins T, Iyer RS, Bobel MA. Growth Hormone and carbohydrate intolerance in cirrhosis.  Horm Metab Res. 1988;  20 579-583
    Suche in Google Scholar
  • 10 Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.  J Clin Invest. 2002;  109 1321-1326
    Suche in Google Scholar
  • 11 Hotamisligl GS. Inflammatory pathways and insulin action.  Int J Obes Rel Metab Disord. 2003;  27 ((Suppl 3)) 553-555
    Suche in Google Scholar
  • 12 Hotamisligil GS. Mechanisms of TNF-α induced insulin resistance.  Exp Clin Endocrinol Diabetes. 1999;  107 119-125
    Suche in Google Scholar
  • 13 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. 1996;  274 1377-1379
    Suche in Google Scholar
  • 14 Kirwan, JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Houston-Presley L, Friedman JE, Kalhan SC, Catalano PM. TNA-α is a predictor of insulin resistance in human pregnancy.  Diabetes. 2002;  51 2207-2213
    Suche in Google Scholar
  • 15 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;  31 1188-1193
    Suche in Google Scholar
  • 16 Ruan H, Miles PD, Ladd CM, Ross K, Golub TR, Olefsky JM, Lodish HF. Profiling gee transcription in vivo reveals adipose tissue as an immediate target of TNF-α.  Diabetes. 2002;  51 3176-3188
    Suche in Google Scholar
  • 17 Hotamisligil GS, Arne P, Caro JF, Atkinson RL. Speigelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.  J Clin Invest. 1995;  95 2409-2414
    Suche in Google Scholar
  • 18 Kern PA, Sagizadeh M, Ong JM, Bosch RJ, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue.  J Clin Invest. 1995;  95 2111-2119
    Suche in Google Scholar
  • 19 Cheung AT, Ree D, Kolls JK, Fuselier J, Coy DH, Bryer-Ash M. An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: Evidence for differential regulation of insulin signaling by TNF-alpha.  Endocrinology. 1998;  139 4928-4935
    Suche in Google Scholar
  • 20 Hotamisligil GS, Perald, 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. 1996;  271 665-668
    Suche in Google Scholar
  • 21 Solomon SS, Buss N, Shull J, Monnier S, Majumdar G, Wu J, Gerling IC. Proteome of H-411E (liver) cells exposed to insulin and TNF-α: Analysis of proteins involved in insulin resistance.  J Lab Clin Med. 2005;  145 275-283
    Suche in Google Scholar
  • 22 Solomon SS, Mishra SK, Cwik C, Rajanna B, Postlethwaite AE. Pioglitazone and metformin reverse insulin resistance induced by tumor necrosis factor-alpha in liver cells.  Horm Metab Res. 1997;  29 379-382
    Suche in Google Scholar
  • 23 Peraldi P, Hotamisligil GS, Burman WA, White MF, Spiegelman BM. Tumor necrosis factor-alpha (TNF-α) inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomylenase.  J Biol Chem. 1996;  271 13018-130122
    Suche in Google Scholar
  • 24 Solomon SS, Mishra SK, Palazzolo MR, Postlethwaite AE, Seyer JM. Identification of specific sites in the TNF-α molecule promoting insulin resistance in H-411E cells.  J Lab Clin Med. 1997;  130 139-146
    Suche in Google Scholar
  • 25 Pang Y, Zheng B, Fan LW, Rhodes PG, Cai Z. IGF-1 protects oligodendrocyte progenitors against TNF-α induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway.  Glia. 2007;  55 1099-1107
    Suche in Google Scholar
  • 26 Gerling IC, Singh S, Lenchik NI, Marshall DR, Wu J. New data-analysis and mining approaches identify unique proteome and transcriptome markers of susceptibility to autoimmune diabetes.  Mol Cell Proteomics. 2006;  5 293-305
    Suche in Google Scholar
  • 27 Gadgill HS, Pabst KM, Giorgianni F, Umstot ES, Desiderio DM, Beranova-Giorgianni S, Gerling IC, Pabst MJ. Proteome of monocytes primed with lipopolysacharide: Analysis of the abundant proteins.  Proteomics. 2003;  3 1767-1780
    Suche in Google Scholar
  • 28 Gerling IC, Ahokas RA, Wodi LA, Bhattacharya SK, Warrington KJ, Postlethwaite AE, Weber KT. Aldosteronism: An immunostimulatory state precedes the pro inflammatory/fibrogenic cardiac phenotype. Amer.  J Physiol- Heart C. 2003;  285 H813-H821
    Suche in Google Scholar
  • 29 Aniquichi CM, Tran TT, Kondo T, Luo J, Veki K, Cauley LC, Kahn CR. PI3 Kinase regulatory subunit P85 α suppresses insulin via positive regulation of PTEN.  Proc Natl Acad Sci U S A. 2006;  103 12093-12097
    Suche in Google Scholar
  • 30 Gustin JA, Machama T, Dixon TE, Donner DB. The PTEN suppressor protein inhibits TNF-induced NFKβ activity.  J Biol Chem. 2001;  276 27740-27744
    Suche in Google Scholar
  • 31 Araújo EP, De Souza CT, Ueno, Mcintra DE, Bertolo MB, Carvalheira JB, Mário J, Velloso LA. Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes.  Endocrinology. 2007;  148 5991-5997
    Suche in Google Scholar
  • 32 Petersen KF, Shulman GI. Etiology of insulin resistance.  Am J Med. 2006;  119 S10-S16
    Suche in Google Scholar
  • 33 Perseghi G, Petersen K, Shulman GI. Cellular mechanism of insulin resistance; potential links with inflammation.  Int J Obes Relat Metab Disord. 2003;  27 ((Suppl 3)) S6-S11
    Suche in Google Scholar
  • 34 Petersen KF, Hendler R, Price T, Perseghin G, Rothman DL, Heid N, Amatruda JM, Shulman GI. 13C/31P NMR studies on the mechanism of insulin resistance in Obesity.  Diabetes. 1998;  47 381-386
    Suche in Google Scholar
  • 35 Steinberg GR, Mitchell BJ, Van Denderen BJ, Watt MJ, Carey AL, Fam BC, Andrickopoulos S, Proietto J, Gorgun CZ, Carling D, Hotamisligil GS, Febbraio MA, Kay TW, Kemp BE. Tumor necrosis factor-alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling.  Cell Metab. 2006;  4 465-474
    Suche in Google Scholar
  • 36 Befroy DE, Petersen KF, Dufour S, Mason GF, DeFraaf RA, Rothman DL, Shulman GI. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of Type 2 diabetic patients.  Diabetes. 2007;  56 1376-1381
    Suche in Google Scholar
  • 37 Nishikawa T, Aroki E. Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications.  Antoxid Redox Signal. 2007;  9 343-353
    Suche in Google Scholar
  • 38 Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Tsuruzoe K. Impact of mitochondrial reactive oxygen species and apoptosis signal regulating kinase 1 on insulin signaling.  Diabetes. 2006;  55 1197-1204
    Suche in Google Scholar
  • 39 James KA, Albeck JG, Gaudet S, Sorger PK, Lauftenburger DA, Yatte MD. A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis.  Science. 2005;  310 1646-1653
    Suche in Google Scholar
  • 40 Qin B, Dawson H, Polansky MM, Anderson RA. Cinnamon extract attenuates TNF-α-induced Intestinal lipoprotein Apo B48 overproduction by regulating inflammatory, insulin, and lipoprotein pathways in enterocytes.  Horm Metab Res. 2009;  41 516-522
    Suche in Google Scholar

Correspondence

S. S. SolomonMD 

Division of Endocrinology University of Tennessee Health Science Center

VAMC Research 151

1030 Jefferson Avenue

TN 38104 Memphis

USA

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Fax: +1 901 577 7273

eMail: ssolomon@utmem.edu