Abstract
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.
Similar content being viewed by others
References
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 92:2272–2279
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 29:1303–1310
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 257:79–83
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 43:783–790
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953
Bornstein SR, Preas HL, Chrousos GP, Suffredini AF (1998) Circulating leptin levels during acute experimental endotoxemia and antiinflammatory therapy in humans. J Infect Dis 178:887–890
Brahimi-Horn MC, Pouysségur J (2007) Oxygen, a source of life and stress. FEBS Lett 581:3582–3591
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 341:549–556
Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356
Ellis CG, Jagger J, Sharpe M (2005) The microcirculation as a functional system. Crit Care 9(Suppl 4):S3–S8
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–R208
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 97:2152–2157
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 74:1704–1710
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 60:865–872
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 56:901–911
Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-α—direct role in obesity-linked insulin resistance. Science 259:87–91
Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue LW 3rd, Bland KI, Chaudry IH (2005) Cecal ligation and puncture. Shock 24(Suppl 1):52–57
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–E379
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 311:372–379
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 38:701–710
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 275:24255–24263
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 27:1187–1195
Mannel DN (2007) Advances in sepsis research derived from animal models. Int J Med Microbiol 297:393–400
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 23:286–292
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 82:4196–4200
Moller DE (2000) Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11:212–217
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 100:2473–2476
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 102:1296–1301
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–E339
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 46:1939–1944
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 32:451–463
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 127:2125–2131
Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847–853
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 278:45777–45784
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 318:168–175
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 185:171–175
Sartipy P, Loskutoff DJ (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270
Schumacker PT (2005) Hypoxia-inducible factor-1 (HIF-1). Crit Care Med 33:S423–S425
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 475:123–130
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 152:863–868
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 346:739–745
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 199:171–179
Torpy DJ, Bornstein SR, Chrousos GP (1998) Leptin and interleukin-6 in sepsis. Horm Metab Res 30:726–729
Trayhurn P (2005) Endocrine and signalling role of adipose tissue: new perspectives on fat. Acta Physiol Scand 184:285–293
Trayhurn P, Wood IS (2004) Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355
Trayhurn P, Wood IS (2005) Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 33:1078–1081
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 345:1359–1367
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–E740
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 452:418–427
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 455:479–492
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 112:1796–1808
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 337:422–429
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 112:1821–1830
Yaegashi M, Jean R, Zuriqat M, Noack S, Homel P (2005) Outcome of morbid obesity in the intensive care unit. J Intensive Care Med 20:147–154
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 7:941–946
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–E1128
Acknowledgement
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Leuwer, M., Welters, I., Marx, G. et al. Endotoxaemia leads to major increases in inflammatory adipokine gene expression in white adipose tissue of mice. Pflugers Arch - Eur J Physiol 457, 731–741 (2009). https://doi.org/10.1007/s00424-008-0564-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-008-0564-8