Abstract
The pro-inflammatory cytokine TNF-α has multiple effects on adipocyte function, including the production of adipokines. In this paper, we have examined the acute vs prolonged effects of TNF-α on the expression and secretion of key inflammation-related adipokines by human adipocytes. Adipocytes differentiated in culture were treated with TNF-α for 1–24 h, mRNA quantitated by real-time polymerase chain reaction (PCR) and secreted adipokines by ELISA. Treatment of adipocytes with TNF-α for up to 24 h had little effect on MIF, MT-2 and PAI-1 mRNA levels. TNF-α decreased adiponectin, adipsin, haptoglobin and leptin mRNA levels by 24 h, but adiponectin and haptoglobin mRNA was initially increased. In contrast, TNF-α induced rapid and substantial increases in expression of the genes encoding IL-6, MCP-1, NGF and TNF-α itself; IL-6 and TNF-α mRNA levels peaked at 2 h with 75-fold and 600-fold increases, respectively. The elevated MCP-1, NGF and VEGF mRNA levels were sustained between 4 and 24 h. The adipokine secretion pattern largely paralleled cellular mRNA levels; IL-6 (transiently), MCP-1, NGF and VEGF release were stimulated by TNF-α, with an accelerating rate of MCP-1 secretion over 24 h. TNF-α has rapid and substantial effects on the synthesis of key inflammation-related adipokines in human adipocytes, with highly gene-specific responses.
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Abbreviations
- IL-6:
-
Interleukin-6
- MCP-1:
-
Monocyte chemoattractant protein-1
- MIF:
-
Macrophage migration inhibitory factor
- MT-2:
-
Metallothionein-2
- NGF:
-
Nerve growth factor
- PAI-1:
-
Plasminogen activator inhibitor-1
- TNF-α:
-
Tumour necrosis factor-α
- VEGF:
-
Vascular endothelial growth factor
References
Bartness TJ, Bamshad M (1998) Innervation of mammalian white adipose tissue: implications for the regulation of total body fat. Am J Physiol Regul Integr Comp Physiol 44:R1399–R1411
Cigolini M, Tonoli M, Borgato L, Frigotto L, Manzato F, Zeminian S, Cardinale C, Camin M, Chiaramonte E, DeSandre G, Lunardi C (1999) Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-α? Atherosclerosis 143:81–90
Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356
Cousin B, Casteilla L, Lafontan M, Ambid L, Langin D, Berthault MF, Penicaud L (1993) Local sympathetic denervation of white adipose tissue in rats induces preadipocyte proliferation without noticeable changes in metabolism. Endocrinology 133:2255–2262
Fasshauer M, Paschke R (2003) Regulation of adipocytokines and insulin resistance. Diabetologia 46:1594–1603
Fasshauer M, Klein J, Lossner U, Paschke R (2003) Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes. Horm Metab Res 35:147–152
Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R (2002) Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 290:1084–1089
Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R (2003) Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 301:1045–1050
Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770
Frühbeck G, Gómez-Ambrosi J, Muruzabal FJ, Burrell MA (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280:E827–E847
Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD (2001) Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 175:81–92
Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ (2001) The biology of white adipocyte proliferation. Obes Rev 2:239–254
He G, Bruun JM, Lihn AS, Pedersen SB, Richelsen B (2003) Stimulation of PAI-1 and adipokines by glucose in human adipose tissue in vitro. Biochem Biophys Res Commun 310:878–883
Hirokawa J, Sakaue S, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J (1997) Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-α. Biochem Biophys Res Commun 235:94–98
Hotamisligil GS (2003) Inflammatory pathways and insulin action. Int J Obes 27(Suppl 3):S53–S55
Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703
Kappes A, Loffler G (2000) Influences of ionomycin, dibutyryl-cycloAMP and tumour necrosis factor-α on intracellular amount and secretion of apM1 in differentiating primary human preadipocytes. Horm Metab Res 32:548–554
Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:E745–E751
Kirchgessner TG, Uysal K, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Tumor necrosis factor-α contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest 100:2777–2782
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
Lofgren P, van Harmelen V, Reynisdottir S, Naslund E, Ryden M, Rossner S, Arner P (2000) Secretion of tumor necrosis factor-α shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. Diabetes 49:688–692
Lolmede K, Durand de Saint Front V, Galitzky J, Lafontan M, Bouloumie A (2003) Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes 27:1187–1195
Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y (2001) PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094–2099
Mick GJ, Wang X, McCormick K (2002) White adipocyte vascular endothelial growth factor: regulation by insulin. Endocrinology 143:948–953
Moller DE (2000) Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11:212–217
Nomura S, Shouzu A, Omoto S, Nishikawa M, Fukuhara S (2000) Significance of chemokines and activated platelets in patients with diabetes. Clin Exp Immunol 121:437–443
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
Qi C, Pekala PH (2000) Tumor necrosis factor-α-induced insulin resistance in adipocytes. Proc Soc Exp Biol Med 223:128–135
Rajala MW, Scherer PE (2003) Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773
Ryden M, Arvidsson E, Blömqvist L, Perbeck L, Dicker A, Arner P (2004) Targets for TNF-α-induced lipolysis in human adipocytes. Biochem Biophys Res Commun 318:168–175
Sakamoto T, Woodcock-Mitchell J, Marutsuka K, Mitchell JJ, Sobel BE, Fujii S (1999) TNF-α and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes. Am J Physiol Cell Physiol 45:C1391–C1397
Sartipy P, Loskutoff DJ (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270
Sethi JK, Hotamisligil GS (1999) The role of TNFα in adipocyte metabolism. Semin Cell Dev Biol 10:19–29
Skurk T, Herder C, Kraft I, Muller-Scholze S, Hauner H, Kolb H (2005) Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 146:1006–1011
Torti FM, Torti SV, Larrick JW, Ringold GM (1989) Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor β. J Cell Biol 108:1105–1113
Trayhurn P, Beattie JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339
Trayhurn P, Wood IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355
Wabitsch M, Brenner RE, Melzner I, Braun M, Moller P, Heinze E, Debatin KM, Hauner H (2001) Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes 25:8–15
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
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
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935
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
Yudkin JS (2003) Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obes 27(Suppl 3):S25–S28
Zhang HH, Kumar S, Barnett AH, Eggo MC (2000) Tumour necrosis factor-α exerts dual effects on human adipose leptin synthesis and release. Mol Cell Endocrinol 159:79–88
Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homolog. Nature 372:425–432
Acknowledgements
We are grateful to Mr. Leif Hunter for his help, to Dr John Jenkins for access to the ABI PRISM 7700 and to Prof. Martin Wabitsch (University of Ulm) for supplying SGBS cells. This work was funded by the European Union Framework 5 Programme (OB-AGE: OLK6-CT-2002-02288).
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Wang, B., Trayhurn, P. Acute and prolonged effects of TNF-α on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Pflugers Arch - Eur J Physiol 452, 418–427 (2006). https://doi.org/10.1007/s00424-006-0055-8
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DOI: https://doi.org/10.1007/s00424-006-0055-8