Pflügers Archiv - European Journal of Physiology

, Volume 457, Issue 4, pp 731–741 | Cite as

Endotoxaemia leads to major increases in inflammatory adipokine gene expression in white adipose tissue of mice

  • Martin Leuwer
  • Ingeborg Welters
  • Gernot Marx
  • Andrew Rushton
  • Hongguang Bao
  • Leif Hunter
  • Paul Trayhurn
Integrative Physiology


The proposition that white adipose tissue is involved in the inflammatory response and metabolic dysregulation of endotoxaemia has been examined. Mice were injected with lipopolysaccharide (LPS; 25 mg/kg) and epididymal, perirenal and subcutaneous adipose tissue removed 4 or 24 h later. The expression of genes encoding key inflammation-related adipokines was measured by real-time polymerase chain reaction. At 24 h after the administration of LPS, there was no change in leptin mRNA level, and adiponectin mRNA fell. However, major increases in TNFα, MCP-1 (up to 40-fold) and IL-6 (up to 250-fold) mRNA levels were evident; a substantial elevation in these mRNAs occurred by 4 h, and adipose tissue IL-6 protein also increased (three- to eightfold). At 24 h, the responses in the subcutaneous depot were much lower than in epididymal and perirenal adipose tissue, but at 4 h, the subcutaneous tissue showed major increases in IL-6, MCP-1 and TNFα gene expression. In contrast to the inflammatory adipokines, the mRNA level of two macrophage markers, F4/80 and MAC-1, was unaltered in adipose tissue during endotoxaemia. Expression of the hypoxia-sensitive transcription factor, HIF-1α, gene was increased at both 4 and 24 h, and HIF-1α protein was elevated at 4 h, suggesting that the tissue was hypoxic. It is concluded that white adipose tissue may play an important role in the production of inflammatory mediators in endotoxaemia.


Adipokines Adipose tissue Endotoxaemia IL-6 Inflammation Sepsis 



We gratefully acknowledge the receipt of funding from the Biotechnology and Biological Sciences Research Council (UK) to PT. The authors declare that they have no conflicts of interest with respect to this study. PT is a member of COST BM0602.


  1. 1.
    Anderson PD, Mehta NN, Wolfe ML, Hinkle CC, Pruscino L, Comiskey LL, Tabita-Martinez J, Sellers KF, Rickels MR, Ahima RS, Reilly MP (2007) Innate immunity modulates adipokines in humans. J Clin Endocrinol Metab 92:2272–2279PubMedCrossRefGoogle Scholar
  2. 2.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310PubMedCrossRefGoogle Scholar
  3. 3.
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83PubMedCrossRefGoogle Scholar
  4. 4.
    Barbier M, Cherbut C, Aube AC, Blottiere HM, Galmiche JP (1998) Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats. Gut 43:783–790PubMedCrossRefGoogle Scholar
  5. 5.
    Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953PubMedCrossRefGoogle Scholar
  6. 6.
    Bornstein SR, Preas HL, Chrousos GP, Suffredini AF (1998) Circulating leptin levels during acute experimental endotoxemia and antiinflammatory therapy in humans. J Infect Dis 178:887–890PubMedGoogle Scholar
  7. 7.
    Brahimi-Horn MC, Pouysségur J (2007) Oxygen, a source of life and stress. FEBS Lett 581:3582–3591PubMedCrossRefGoogle Scholar
  8. 8.
    Chen B, Lam KSL, Wang Y, Wu D, Lam MC, Shen J, Wong L, Hoo RLC, Zhang J, Xu A (2006) Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun 341:549–556PubMedCrossRefGoogle Scholar
  9. 9.
    Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356PubMedCrossRefGoogle Scholar
  10. 10.
    Ellis CG, Jagger J, Sharpe M (2005) The microcirculation as a functional system. Crit Care 9(Suppl 4):S3–S8PubMedCrossRefGoogle Scholar
  11. 11.
    Faggioni R, Fantuzzi G, Fuller J, Dinarello CA, Feingold KR, Grunfeld C (1998) IL-1 beta mediates leptin induction during inflammation. Am J Physiol Reg Integr Comp Physiol 43:R204–R208Google Scholar
  12. 12.
    Grunfeld C, Zhao C, Fuller J, Pollock A, Moser A, Friedman J, Feingold KR (1996) Endotoxin and cytokines induce expression of leptin, the ob gene-product, in hamsters—a role for leptin in the anorexia of infection. J Clin Invest 97:2152–2157PubMedCrossRefGoogle Scholar
  13. 13.
    Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack Van Schijndel RJ, Eerenberg-Belmer AJ, Thijs LG, Aarden LA (1989) Increased plasma levels of interleukin-6 in sepsis. Blood 74:1704–1710PubMedGoogle Scholar
  14. 14.
    Heuer JG, Sharma GR, Zhang T, Ding C, Bailey DL, Stephens EJ, Holmes KC, Grubbs RL, Fynboe KA, Chen YF, Jakubowski JA (2006) Effects of hyperglycemia and insulin therapy on outcome in a hyperglycemic septic model of critical illness. J Trauma 60:865–872PubMedCrossRefGoogle Scholar
  15. 15.
    Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56:901–911PubMedCrossRefGoogle Scholar
  16. 16.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867PubMedCrossRefGoogle Scholar
  17. 17.
    Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-α—direct role in obesity-linked insulin resistance. Science 259:87–91PubMedCrossRefGoogle Scholar
  18. 18.
    Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue LW 3rd, Bland KI, Chaudry IH (2005) Cecal ligation and puncture. Shock 24(Suppl 1):52–57PubMedCrossRefGoogle Scholar
  19. 19.
    Krogh-Madsen R, Plomgaard P, Akerström T, Moller K, Schmitz O, Pedersen BK (2008) Effect of short-term intralipid infusion on the immune response during low-dose endotoxemia in humans. Am J Physiol Endocrinol Metab 294:E371–E379PubMedCrossRefGoogle Scholar
  20. 20.
    Lagathu C, Bastard J-P, Auclair M, Maachi M, Capeau J, Caron M (2003) Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun 311:372–379PubMedCrossRefGoogle Scholar
  21. 21.
    Lanza-Jacoby S, Sedkova N, Phetteplace H, Perrotti D (1997) Sepsis-induced regulation of lipoprotein lipase expression in rat adipose tissue and soleus muscle. J Lipid Res 38:701–710PubMedGoogle Scholar
  22. 22.
    Lin Y, Lee H, Berg AH, Lisanti MP, Shapiro L, Scherer PE (2000) The lipopolysaccharide-activated toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes. J Biol Chem 275:24255–24263PubMedCrossRefGoogle Scholar
  23. 23.
    Lolmeèe K, Durand de Saint Front V, Galitzky J, Lafontan M, Bouloumié A (2003) Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obesity 27:1187–1195CrossRefGoogle Scholar
  24. 24.
    Mannel DN (2007) Advances in sepsis research derived from animal models. Int J Med Microbiol 297:393–400PubMedCrossRefGoogle Scholar
  25. 25.
    Martinez A, Chiolero R, Bollman M, Revelly JP, Berger M, Cayeux C, Tappy L (2003) Assessment of adipose tissue metabolism by means of subcutaneous microdialysis in patients with sepsis or circulatory failure. Clin Physiol Funct Imaging 23:286–292PubMedCrossRefGoogle Scholar
  26. 26.
    Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J Clin Endocrinol Metab 82:4196–4200PubMedCrossRefGoogle Scholar
  27. 27.
    Moller DE (2000) Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11:212–217PubMedCrossRefGoogle Scholar
  28. 28.
    Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y (1999) Novel modulator for endothelial adhesion molecules—adipocyte-derived plasma protein adiponectin. Circulation 100:2473–2476PubMedGoogle Scholar
  29. 29.
    Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappa B signaling through a cAMP-dependent pathway. Circulation 102:1296–1301PubMedGoogle Scholar
  30. 30.
    Peeraully MR, Jenkins JR, Trayhurn P (2004) NGF gene expression and secretion in white adipose tissue: regulation in 3T3-L1 adipocytes by hormones and inflammatory cytokines. Am J Physiol Endocrinol Metab 287:E331–E339PubMedCrossRefGoogle Scholar
  31. 31.
    Prins JB, Niesler CU, Winterford CM, Bright NA, Siddle K, Orahilly S, Walker NI, Cameron DP (1997) Tumor necrosis factor-α induces apoptosis of human adipose cells. Diabetes 46:1939–1944PubMedCrossRefGoogle Scholar
  32. 32.
    Rausch ME, Weisberg SP, Vardhana P, Tortorielllo DV (2008) Obesity in C57BL/6J mice is characterised by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obesity 32:451–463CrossRefGoogle Scholar
  33. 33.
    Ray DE, Matchett SC, Baker K, Wasser T, Young MJ (2005) The effect of body mass index on patient outcomes in a medical ICU. Chest 127:2125–2131PubMedCrossRefGoogle Scholar
  34. 34.
    Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847–853PubMedCrossRefGoogle Scholar
  35. 35.
    Rotter V, Nagaev I, Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-α, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278:45777–45784PubMedCrossRefGoogle Scholar
  36. 36.
    Ryden M, Arvidsson E, Blomqvist L, Perbeck L, Dicker A, Arner P (2004) Targets for TNF-α-induced lipolysis in human adipocytes. Biochem Biophys Res Commun 318:168–175PubMedCrossRefGoogle Scholar
  37. 37.
    Sarraf P, Frederich RC, Turner EM, Ma G, Jaskowiak NT, Rivet DJ, Flier JS, Lowell BB, Fraker DL, Alexander HR (1997) Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 185:171–175PubMedCrossRefGoogle Scholar
  38. 38.
    Sartipy P, Loskutoff DJ (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270PubMedCrossRefGoogle Scholar
  39. 39.
    Schumacker PT (2005) Hypoxia-inducible factor-1 (HIF-1). Crit Care Med 33:S423–S425PubMedCrossRefGoogle Scholar
  40. 40.
    Semenza GL, Agani F, Feldser D, Iyer N, Kotch L, Laughner E, Yu A (2000) Hypoxia, HIF-1, and the pathophysiology of common human diseases. Adv Exp Med Biol 475:123–130PubMedCrossRefGoogle Scholar
  41. 41.
    Skurk T, Kolb H, Muller-Scholze S, Rohrig K, Hauner H, Herder C (2005) The proatherogenic cytokine interleukin-18 is secreted by human adipocytes. Eur J Endocrinol 152:863–868PubMedCrossRefGoogle Scholar
  42. 42.
    Song MJ, Kim KH, Yoon JM, Kim JB (2006) Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun 346:739–745PubMedCrossRefGoogle Scholar
  43. 43.
    Sugawara K, Miyata G, Shineha R, Satomi S (2003) The lipolytic responsiveness to endotoxin in subcutaneous adipose tissue is greater than mesenteric adipose tissue. Tohoku J Exp Med 199:171–179PubMedCrossRefGoogle Scholar
  44. 44.
    Torpy DJ, Bornstein SR, Chrousos GP (1998) Leptin and interleukin-6 in sepsis. Horm Metab Res 30:726–729PubMedCrossRefGoogle Scholar
  45. 45.
    Trayhurn P (2005) Endocrine and signalling role of adipose tissue: new perspectives on fat. Acta Physiol Scand 184:285–293PubMedCrossRefGoogle Scholar
  46. 46.
    Trayhurn P, Wood IS (2004) Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355PubMedCrossRefGoogle Scholar
  47. 47.
    Trayhurn P, Wood IS (2005) Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 33:1078–1081PubMedCrossRefGoogle Scholar
  48. 48.
    van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359–1367PubMedCrossRefGoogle Scholar
  49. 49.
    Wang B, Jenkins JR, Trayhurn P (2005) Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-α. Am J Physiol Endocrinol Metab 288:E731–E740PubMedCrossRefGoogle Scholar
  50. 50.
    Wang B, Trayhurn P (2006) Acute and prolonged effects of TNF-α on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Pflügers Archiv Eur J Physiol 452:418–427CrossRefGoogle Scholar
  51. 51.
    Wang B, Wood IS, Trayhurn P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflügers Archiv Eur J Physiol 455:479–492CrossRefGoogle Scholar
  52. 52.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808PubMedGoogle Scholar
  53. 53.
    Wood IS, Wang B, Jenkins JR, Trayhurn P (2005) The pro-inflammatory cytokine IL-18 is expressed in human adipose tissue and strongly upregulated by TNFα in human adipocytes. Biochem Biophys Res Commun 337:422–429PubMedCrossRefGoogle Scholar
  54. 54.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830PubMedGoogle Scholar
  55. 55.
    Yaegashi M, Jean R, Zuriqat M, Noack S, Homel P (2005) Outcome of morbid obesity in the intensive care unit. J Intensive Care Med 20:147–154PubMedCrossRefGoogle Scholar
  56. 56.
    Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946PubMedCrossRefGoogle Scholar
  57. 57.
    Ye J, Gao Z, Yin J, He Q (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293:E1118–E1128PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Martin Leuwer
    • 1
  • Ingeborg Welters
    • 1
  • Gernot Marx
    • 3
  • Andrew Rushton
    • 1
  • Hongguang Bao
    • 1
  • Leif Hunter
    • 2
  • Paul Trayhurn
    • 2
  1. 1.Critical Care Research Unit, School of Clinical SciencesUniversity of Liverpool, University Clinical DepartmentsLiverpoolUK
  2. 2.Obesity Biology Research Unit, School of Clinical SciencesUniversity of Liverpool, University Clinical DepartmentsLiverpoolUK
  3. 3.University Clinic for Anaesthesiology and Intensive Care, University of JenaJenaGermany

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