Skip to main content Accessibility help
×
×
Home

Pro-inflammatory cytokines and adipose tissue

  • Simon W. Coppack (a1)

Abstract

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor a (TNF-a) and several interleukins (IL), notably IL-1b and IL-6. Other adipocyte products with ‘immunological’ actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-a and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-a mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual ‘inflammatory‘ stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-a. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-a and IL-6 inhibit lipoprotein lipase, and TNF-a additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-a also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more ‘trophic’, and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor g). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of b3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-a is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-a is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.

    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Pro-inflammatory cytokines and adipose tissue
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Pro-inflammatory cytokines and adipose tissue
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Pro-inflammatory cytokines and adipose tissue
      Available formats
      ×

Copyright

Corresponding author

Corresponding Author: Dr Simon Coppack, fax +44 207 377 7636, email s.w.coppack@mds.qmw.ac.uk

References

Hide All
Bastard, J-P, Jarde, C, Bruckert, E, Blondy, P, Capeau, J, Laville, M, Vidal, H & Hainque, B (2000) Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. Journal of Clinical Endocrinology and Metabolism 85, 33383342.
Berkowitz, DE, Brown, D, Lee, KM, Emala, C, Palmer, D, An, Y & Breslow, M (1998) Endotoxin-induced alteration in the expression of leptin and b3-adrenergic receptor in adipose tissue. American Journal of Physiology 274, E992E997.
Beutler, B, Krochin, N, Milsark, I, Leudke, C & Cerami, A (1986) Control of cachexin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science 232, 977979.
Crawford, EK, Ensor, JE, Kalvakolanu, I & Hasday, JD (1997) The role of 3ç poly(A) tail metabolism in tumor necrosis factor-alpha regulation. Journal of Biological Chemistry 272, 2112021127.
Fawcett, RL, Waechter, AS, Williams, LB, Zhang, P, Louie, R, Jones, R, Inman, M, Huse, J & Considine, RV (2000) Tumor necrosis factor-a inhibits leptin production in subcutaneous and omental adipocytes from morbidly obese humans. Journal of Clinical Endocrinology and Metabolism 85, 530535.
Feingold, KR & Grunfeld, C (1992) Role of cytokines in inducing hyperlipidemia. Diabetes 41, Suppl. 2, 97101.
Feingold, KR, Staprans, I, Memon, RA, Moser, AH, Shigenaga, JK, Doerrler, W, Dinarello, CA & Grunfeld, C (1992) Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance. Journal of Lipid Research 33, 17651776.
Fried, SK, Bunkin, DA & Greenberg, AS (1998) Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot differences and regulation by glucocorticoid. Journal of Clinical Endocrinology and Metabolism 83, 847850.
Fried, SK & Zechner, R (1989) Cachectin/tumor necrosis factor decreases human adipose tissue lipoprotein lipase mRNA levels, synthesis, and activity. Journal of Lipid Research 30, 19171923.
Friedman, JM (2000) Obesity in the new millennium. Nature 404, 632634.
Gearing, A, Beckett, P, Christodoulou, M, Churchill, M, Clements, J, Davidson, AH, Drummond, AH, Galloway, WA, Gilbert, R, Gordon, JL, Leber, TM, Mangan, M, Miller, K, Nayee, P, Owen, K, Patel, S, Thomas, W, Wells, G, Wood, LM & Woolley, K (1994) Processing of tumor necrosis factor-a precursor by metalloproteinases. Nature 370, 555557.
Greenberg, AS, Nordan, RP, McIntosh, J, Calvo, JC, Scow, RO & Jablons, D (1992) Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L 1 adipocytes: a possible role for interleukin 6 in cancer cachexia. Cancer Research 52, 41134116.
Grunfeld, C, Zhao, J, Fuller, J, Pollack, A, Moser, A, Friedman, JE & Feingold, KR (1996) Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. Journal of Clinical Investigation 97, 21522157.
Hardardottir, I, Grunfeld, C & Feingold, KR (1994) Effects of endotoxin and cytokines on lipid metabolism. Current Opinion in Lipidology 5, 207215.
Hauner, H, Bender, M, Haastert, B & Hube, F (1998) Plasma concentrations of soluble TNF-alpha receptors in obese patients. International Journal of Obesity and Related Metabolic Disorders 22, 12391243.
Hauner, H, Petruschke, T, Russ, M & Eckel, J (1995) Effects of tumour necrosis factor alpha (TNF) on glucose transport and lipid metabolism of newly-differentiated human fat cells in cell culture. Diabetologia 38, 764771.
Hotamisligil, GS, (1999) The role of TNFa and TNF receptors in obesity and insulin resistance. Journal of Internal Medicine 245, 621625.
Hotamisligil, GS, Arner, P, Atkinson, RL & Spiegelman, BM (1997) Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes 46, 451455.
Hotamisligil, GS, Arner, P, Caro, JF, Atkinson, RL & Spiegelman, BM (1995) Increased adipose tissue expression of tumor necrosis factor-a in human obesity and insulin resistance. Journal of Clinical Investigation 95, 24092415.
Hotamisligil, GS, Budavari, A, Murray, D & Spiegelman, BM (1994) Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. Journal of Clinical Investigation 94, 15431549.
Hotamisligil, GS, Johnson, RS, Distel, RJ, Ellis, R, Papaioannou, VE & Spiegelman, BM (1996a) Uncoupling of obesity from insulin resistance through a targetted mutation in aP2, the adipocyte fatty acid binding protein. Science 274, 13771379.
Hotamisligil, GS, Peraldi, P, Budavari, A, Ellis, R, White, MF & Spiegelman, BM (1996b) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α-and obesity-induced insulin resistance. Science 271, 665668.
Hotamisligil, GS, Shargill, NS & Spiegelman, BM (1993) Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 8791.
Hube, F, Birgel, M, Lee, Y-M, & Hauner, H (1999a) Expression pattern of tumour necrosis factor receptors in subcutaneous and omental human adipose tissue: role of obesity and non-insulin dependent diabetes mellitus. European Journal of Clinical Investigation 29, 672678.
Hube, F & Hauner, H (1999) The role of TNF-α in human adipose tissue: prevention of weight gain at the expense of insulin resistance. Hormone and Metabolic Research 31, 626631.
Hube, F, Lee, Y-M, Rohrig, K & Hauner, H (1999b) The phosphodiesterase inhibitor IBMX suppresses TNF-α expression in human adipocyte precursor cells: a possible explanation for its adipogenic effect. Hormone and Metabolic Research 31, 359362.
Jain, RG, Meredith, MJ & Pekala, PH (1998) Tumor necrosis factor-alpha mediated activation of signal transduction cascades and transcription factors in 3T3-L1 adipocytes. Advances in Enzyme Regulation 38, 333347.
Jain, RG, Phelps, KD & Pekala, PH (1999) Tumor necrosis factor-alpha initiated signal transduction in 3T3-L1 adipocytes. Journal of Cell Physiology 179, 5866.
Jones, JH & Kennedy, RI (1993) Cytokines and hypothalamic-pituitary function. Cytokine 5, 531538.
Jones, TH (1994) Interleukin-6 an endocrine cytokine. Clinical Endocrinology 40, 703713.
Kanety, H, Hemi, R, Papa, MZ & Karasik, A (1996) Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1. Journal of Biological Chemistry 271, 98959897.
Kawakami, M, Pekala, PH, Lane, DM & Cerami, A (1982) Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. Proceedings of the National Academy of Sciences USA 79, 912916.
Kern, PA, Saghizadeh, M, Ong, JM, Bosch, RJ, Deem, R & Simsolo, RB (1995) The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. Journal of Clinical Investigation 95, 21112119.
Kirchgessner, TG, Uysal, KT, Weisbrock, SM, Marino, MW & Hotamisligil, GS (1997) Tumor necrosis factor-a contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. Journal of Clinical Investigation 100, 27772782.
Lawrence, VJ & Coppack, SW (2000) The endocrine function of the fat cell – regulation by the sympathetic nervous system. Hormone and Metabolic Research 32, 453467.
Ledgerwood, EC, Prins, JB, Bright, NA, Johnson, DR, Wolfreys, K, Pober, JS, O'Rahilly, S & Bradley, JR (1998) Tumor necrosis factor is delivered to mitochondria where a tumor necrosis factor-binding protein is localised. Laboratory Investigation 78, 15831589.
Liu, LS, Spelleken, M, Rohrig, K, Hauner, H & Eckel, J (1998) Tumour necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. Diabetes 47, 515522.
McDermott, MF (2001) TNF and TNFR biology in health and disease. Cellular and Molecular Biology (In the Press).
Mattacks, CA & Pond, CM (1999) Interactions of noradrenalin and tumour necrosis factor a, interleukin 4 and interleukin 6 in the control of lipolysis from adipocytes around lymph nodes. Cytokine 11, 334346.
Mohamed-Ali, V, Goodrick, SJ, Bulmer, K, Holley, JMP, Yudkin, JS & Coppack, SW (1999) Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo. American Journal of Physiology 277, E971E975.
Mohamed-Ali, V, Goodrick, SJ, Rawesh, A, Miles, JM, Katz, DR, Yudkin, JS, Klein, S & Coppack, SW (1997) Subcutaneous adipose tissue secretes interleukin-6 but not tumour necrosis factor-a in vivo. Journal of Clinical Endocrinology and Metabolism 82, 41964200.
Mohamed-Ali, V, Pinkney, JH & Coppack, SW (1998) Adipose tissue as an endocrine and paracrine organ. International Journal of Obesity and Related Metabolic Disorders 22, 11451158.
Montague, CT, Prins, JB, Sanders, L, Zhang, J, Sewter, CP, Digby, J, Byrne, CD & O'Rahilly, S (1998) Depot-related gene expression in human subcutaneous and omental adipocytes. Diabetes 47, 13841391.
Morin, CL, Eckel, RH, Marcel, T & Pagliassotti, MJ (1997a) High fat diets elevate adipose tissue-derived tumor necrosis factor-alpha activity. Endocrinology 138, 46654671.
Morin, CL, Pagliassotti, MJ, Windmiller, D & Eckel, RH (1997b) Adipose tissue-derived tumor necrosis factor-alpha activity is elevated in older rats. Journal of Gerontology 52, B190B195.
Mullberg, J, Durie, FH, Otten-Evans, C, Alderson, MR, Rose-John, S, Cosman, D, Black, RA & Mohler, KM (1995) A metalloproteinase inhibitor blocks shedding of the IL-6 receptor and the p60 tumor necrosis factor receptor. Journal of Immunology 155, 51985205.
Niesler, CU, Siddle, K & Prins, JB (1998) Human preadipocytes display a depot-specific susceptibility to apoptosis. Diabetes 47, 13651368.
Niesler, CU, Urso, B, Prins, JB & Siddle, K (2000) IGF-1 inhibits apoptosis induced by serum withdrawal, but potentiates TNF-α-induced apoptosis in 3T3-L1 adipocytes. Journal of Endocrinology 167, 165174.
Nisoli, E, Briscini, L, Giordano, A, Tonello, C, Weisbrock, SM, Uysal, KT, Cinti, S, Carruba, MO & Hotamisligil, GS (2000a) Tumor necrosis factor a mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity. Proceedings of the National Academy of Sciences USA 97, 80338038.
Nisoli, E, Carruba, MO, Tonello, C, Macor, C, Federspil, G & Vettor, R (2000b) Induction of fatty acid translocase/CD36, peroxisome proliferator-activated receptor-γ2, leptin, uncoupling proteins 2 and 3, and tumor necrosis factor-α gene expression in human sub-cutaneous fat by lipid infusion. Diabetes 49, 319324.
Ofei, F, Hurel, S, Newkirk, J, Sopwith, M & Taylor, R (1996) Effects of an engineered human anti-TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45, 881885.
Ogawa, H, Nielsen, S & Kawakami, M (1989) Cachetin/tumor necrosis factor and interleukin-1 show different modes of combined effect on lipoprotein lipase and intracellular lipolysis. Biochimica et Biophysica Acta 1003, 131135.
Papanicolaou, DA, Wilder, RL, Manolagas, SC & Chrousos, GP (1998) The pathophysiologic roles of interleukin-6 in human disease. Annals of Internal Medicine 128, 127137.
Pekala, PH, Kawakami, M, Angus, CW, Lane, MD & Cerami, A (1983) Selective inhibition of synthesis of enzymes for de novo fatty acid biosynthesis by an endotoxin-induced mediator from exudate cells. Proceedings of the National Academy of Sciences USA 80, 27432747.
Peraldi, P, Hotamisligil, GS, Buurman, WA, White, MF & Spiegelman, BM (1997a) Tumor necrosis factor (TNF)-α inhibits insulin signalling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. Journal of Biological Chemistry 271, 1301813022.
Peraldi, P, Xu, M & Spiegelman, BM (1997b) Thiazolidinediones block tumor necrosis factor-α-induced inhibition of insulin signaling. Journal of Clinical Investigation 100, 18631869.
Petruschke, T & Hauner, H (1993) Tumor necrosis factor-alpha prevents the differentiation of human adipocyte precursor cells and causes delipidation of newly developed fat cells. Journal of Clinical Endocrinology and Metabolism 76, 742747.
Plata-Salaman, CR (2000) Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition 16, 10091012.
Pond, CM (1999) Physiological specialisation of adipose tissue. Progress in Lipid Research 38, 225248.
Pond, CM (2001) Long-term changes in adipose tissue in human disease. Proceedings of the Nutrition Society 60, 365374.
Prins, JB, Niesler, CU, Winterford, CM, Bright, NA, Siddle, K, O'Rahilly, S, Walker, NI & Cameron, DP (1997) Tumor necrosis factor-a induces apoptosis of human adipose cells. Diabetes 46, 19391944.
Prins, JB & O'Rahilly, S (1997) Regulation of adipose cell number in man. Clinical Science 92, 311.
Purohit, A, Ghilchik, MW, Duncan, L, Wang, DY, Singh, A, Walker, MM & Reed, MJ (1995) Aromatase activity and interleukin-6 production by normal and malignant breast tissues. Journal of Clinical Endocrinology and Metabolism 80, 30523058.
Qi, C & Pekala, PH (2000) Tumor necrois factor-α-induced insulin resistance in adipocytes. Proceedings of the Society for Experimental Biology and Medicine 223, 128135.
Rothwell, NJ (1994) CNS regulation of thermogenesis. Critical Reviews in Neurobiology 8, 110.
Saleh, J, Summers, LKM, Cianflone, K, Fielding, BA, Sniderman, AD & Frayn, KN (1998) Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period. Journal of Lipid Research 39, 884891.
Sarraf, P, Frederich, RC, Turner, EM, Ma, G, Jaskowiak, NT, Rivet, DJ 3rd, Flier, JS, Lowell, BB, Fraker, DL & Alexander, HR (1997) Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. Journal of Experimental Medicine 185, 171175.
Sethi, JK, Xu, H, Uysal, KT, Wiesbrock, SM, Scheja, L & Hotamisligil, GS (2000) Characterisation of receptor-specific TNFalpha functions in adipocyte cell lines lacking type 1 and 2 TNF receptors. FEBS Letters 469, 7782.
Sewter, CP, Digby, JE, Blows, F, Prins, JB & O'Rahilly, S (1999) Regulation of tumour necrosis factor-alpha release from human adipose tissue in vitro. Journal of Endocrinology 163, 3338.
Stephens, JM, Butts, MD & Pekala, PH (1992) Regulation of transcription factor mRNA accumulation during 3T3-L1 preadipocyte differentiation by tumor necrosis factor-alpha. Journal of Molecular Endocrinology 9, 6172.
Stephens, JM & Pekala, PH (1991) Transcriptional regression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. Journal of Biological Chemistry 266, 2183921845.
Strassmann, G, Fong, M, Windsor, S & Neta, R (1993) The role of interleukin-6 in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production in vivo. Cytokine 5, 285290.
Strosberg, AD & Pietri-Rouxel, F (1996) Function and regulation of the beta3-adrenoceptor. Trends in Pharmacological Science 17, 373381.
Sumida, M, Shiosaka, T, Nagar, A, Isshikimasuda, M, Okuda, H & Hamada, M (1997) Suppressive effect of tumor necrosis factor-a on adipogenic cell differentiation and on gene expression of hormone-sensitive lipase. Journal of Clinical Biochemistry and Nutrition 22, 111.
Szalkowski, D, White-Carrington, S, Berger, J & Zhang, B (1995) Antidiabetic thiazolidinediones block the inhibitory effect of tumour necrosis factor-α on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. Endocrinology 136, 14741481.
Torti, FM, Torti, SV, Larrick, JW & Ringold, GM (1989) Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor. Journal of Cell Biology 108, 11051113.
Uysal, KT, Wiesbrock, SM & Hotamisligil, GS (1998) Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 139, 48324838.
Uysal, KT, Wiesbrock, SM, Marino, MW & Hotamisligil, GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610614.
Van der Poll, T, Romijn, JA, Endert, E, Borm, JJ, B¨ller, HR & Sauerwein, HP (1991) TNF mimics the metabolic response of acute infections in healthy humans. American Journal of Physiology 261, E457E465.
Ventre, J, Doebber, T, Wu, M, MacNaul, K, Stevens, K, Pasparakis, M, Kollias, G & Moller, DE (1997) Targeted disruption of the tumour necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. Diabetes 46, 15261531.
Yudkin, JS, Kumari, M, Humphries, SE & Mohamed-Ali, V (2000) Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148, 209214.
Zhang, B, Berger, J, Hu, E, Szalkowski, D, White-Carrington, S, Spiegelman, BM & Moller, DE (1996) Negative regulation of peroxisome proliferator-activated receptor-g gene expression contributes to the antiadipogenic effects of tumor necrosis factor-α. Molecular Endocrinology 10, 14571466.
Zhang, Y, Proenca, R, Maffei, M, Barone, M, Leopold, L & Friedman, JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425432 (published erratum appears in Nature 374, 479).
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Proceedings of the Nutrition Society
  • ISSN: 0029-6651
  • EISSN: 1475-2719
  • URL: /core/journals/proceedings-of-the-nutrition-society
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed