Vol. 55, No. 4, 2009
Issue release date: July 2009
Free Access
Gerontology 2009;55:379–386
Clinical Section
Add to my selection

Obesity, Inflammation, and Insulin Resistance – A Mini-Review

Zeyda M. · Stulnig T.M.
Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
email Corresponding Author

 goto top of outline Key Words

  • Obesity
  • Adipose tissue
  • Inflammation
  • Macrophages
  • Insulin resistance
  • Type 2 diabetes mellitus

 goto top of outline Abstract

The association of obesity, insulin resistance, and chronic low-grade inflammation has been evident for several years by now. Since obesity, insulin resistance, and inflammation all are related to aging as well, the mechanisms underlying this association are of critical importance for gerontology. Although several molecular and cellular mechanisms by which inflammatory events decrease the sensitivity to insulin in obese patients have recently been elucidated, the pathogenesis of obesity-induced insulin resistance is still obscure in many aspects. This review aims at giving a general view on the known mechanisms and summarizing the recent progress. Research currently focuses on adipose tissue inflammation as predominantly driven by adipose tissue macrophages, but also related alterations in other organs (liver, muscle, pancreas) have to be considered. Moreover, novel approaches for treatment and prevention of insulin resistance and type 2 diabetes by targeting obesity-induced inflammatory processes are discussed here.

Copyright © 2009 S. Karger AG, Basel

 goto top of outline References
  1. Lechleitner M: Obesity and the metabolic syndrome in the elderly – a mini-review. Gerontology 2008;54:253–259.
  2. Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 1998;395:763–770.
  3. Kiefer FW, Zeyda M, Todoric J, Huber J, Geyeregger R, Weichhart T, Aszmann O, Ludvik B, Silberhumer GR, Prager G, Stulnig TM: Osteopontin expression in human and murine obesity: extensive local up-regulation in adipose tissue but minimal systemic alterations. Endocrinology 2008;149:1350–1357.
  4. Bruunsgaard H, Pedersen BK: Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 2003;23:15–39.
  5. Kalofoutis C, Piperi C, Zisaki A, Singh J, Harris F, Phoenix D, Alaveras A, Kalofoutis A: Differences in expression of cardiovascular risk factors among type 2 diabetes mellitus patients of different age. Ann NY Acad Sci 2006;1084:166–177.
  6. Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 1993;259:87–91.
  7. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS: Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 1997;389:610–614.
  8. Hotamisligil GS, Peraldi 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.
  9. Shi H, Tzameli I, Bjorbaek C, Flier JS: Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. J Biol Chem 2004;279:34733–34740.
  10. Jager J, Gremeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF: Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 2007;148:241–251.
  11. Weigert C, Hennige AM, Lehmann R, Brodbeck K, Baumgartner F, Schauble M, Haring HU, Schleicher ED: Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J Biol Chem 2006;281:7060–7067.
  12. Franckhauser S, Elias I, Rotter Sopasakis V, Ferre T, Nagaev I, Andersson CX, Agudo J, Ruberte J, Bosch F, Smith U: Overexpression of IL-6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 2008;51:1306–1316.
  13. Pedersen BK, Febbraio MA: Point: Interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol 2007;102:814–816.
  14. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M: IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 2005;11:191–198.
  15. De Taeye BM, Novitskaya T, McGuinness OP, Gleaves L, Medda M, Covington JW, Vaughan DE: Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity. Am J Physiol 2007;293:E713–E725.
  16. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004;306:457–461.
  17. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006;313:1137–1140.
  18. Miller RS, Diaczok D, Cooke DW: Repression of GLUT4 expression by the endoplasmic reticulum stress response in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2007;362:188–192.
  19. Wu D, Ren Z, Pae M, Guo W, Cui X, Merrill AH, Meydani SN: Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J Immunol 2007;179:4829–4839.
  20. Ohman MK, Shen Y, Obimba CI, Wright AP, Warnock M, Lawrence DA, Eitzman DT: Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008;117:798–805.
  21. Fain JN: Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 2006;74:443–477.
  22. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796–1808.
  23. Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Gyori G, Zlabinger GJ, Stulnig TM: Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int J Obes (Lond) 2007;31:1420–1428.
  24. Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D, Coussieu C, Basdevant A, Hen AB, Bedossa P, Guerre-Millo M, Clement K: Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 2006;55:1554–1561.
  25. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS: Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005;46:2347–2355.
  26. Huber J, Kiefer FW, Zeyda M, Ludvik B, Silberhumer GR, Prager G, Zlabinger GJ, Stulnig TM: CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity. J Clin Endocrinol Metab 2008;93:3215–3221.
  27. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa KI, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M: MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116:1494–1505.
  28. Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, Flier JS: Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 2007;56:2242–2250.
  29. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW: CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006;116:115–124.
  30. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR: Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 2007;56:16–23.
  31. Zeyda M, Stulnig TM: Adipose tissue macrophages. Immunol Lett 2007;112:61–67.
  32. Todoric J, Loffler M, Huber J, Bilban M, Reimers M, Kadl A, Zeyda M, Waldhausl W, Stulnig TM: Adipose tissue inflammation induced by high-fat diet in obese diabetic mice is prevented by n–3 polyunsaturated fatty acids. Diabetologia 2006;49:2109–2119.
  33. Lumeng CN, Bodzin JL, Saltiel AR: Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007;117:175–184.
  34. Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD, Vidal H, Laville M, Barsh GS, Basdevant A, Stich V, Cancello R, Langin D: Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J 2004;18:1657–1669.
  35. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS: TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015–3025.
  36. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R: Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761–1772.
  37. Erridge C, Attina T, Spickett CM, Webb DJ: A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 2007;86:1286–1292.
  38. Saito H, Sherwood ER, Varma TK, Evers BM: Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mech Ageing Dev 2003;124:1047–1058.
  39. Kim JH, Kim JE, Liu HY, Cao W, Chen J: Regulation of interleukin-6-induced hepatic insulin resistance by mammalian target of rapamycin through the STAT3-SOCS3 pathway. J Biol Chem 2008;283:708–715.
  40. Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC: C3H/HeJ mice carrying a toll-like receptor-4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 2007;50:1267–1276.
  41. Wunderlich FT, Luedde T, Singer S, Schmidt-Supprian M, Baumgartl J, Schirmacher P, Pasparakis M, Bruning JC: Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci USA 2008;105:1297–1302.
  42. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A: Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab 2008;7:496–507.
  43. Sell H, Eckel J, Dietze-Schroeder D: Pathways leading to muscle insulin resistance – the muscle-fat connection. Arch Physiol Biochem 2006;112:105–113.
  44. Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M: Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 2007;117:1658–1669.
  45. Friedman JE, Kirwan JP, Jing M, Presley L, Catalano PM: Increased skeletal muscle tumor necrosis factor-α and impaired insulin signaling persist in obese women with gestational diabetes mellitus 1 year postpartum. Diabetes 2008;57:606–613.
  46. Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW: Toll Like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 2007;100:1589–1596.
  47. Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, Gueripel X, Ellingsgaard H, Schneider MK, Biollaz G, Fontana A, Reinecke M, Homo-Delarche F, Donath MY: Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 2007;56:2356–2370.
  48. Maedler K, Schulthess FT, Bielman C, Berney T, Bonny C, Prentki M, Donath MY, Roduit R: Glucose and leptin induce apoptosis in human β-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases. FASEB J 2008;22:1905–1913.
  49. Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY: Glucose-induced β-cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002;110:851–860.
  50. Fleischman A, Shoelson SE, Bernier R, Goldfine AB: Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 2008;31:289–294.
  51. Zu L, Jiang H, He J, Xu C, Pu S, Liu M, Xu G: Salicylate blocks lipolytic actions of tumor necrosis factor-α in primary rat adipocytes. Mol Pharmacol 2008;73:215–223.
  52. Zeender E, Maedler K, Bosco D, Berney T, Donath MY, Halban PA: Pioglitazone and sodium salicylate protect human β-cells against apoptosis and impaired function induced by glucose and interleukin-1β. J Clin Endocrinol Metab 2004;89:5059–5066.
  53. Beraza N, Malato Y, Vander Borght S, Liedtke C, Wasmuth HE, Dreano M, de Vos R, Roskams T, Trautwein C: Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 2008;57:655–663.
  54. Solinas G, Naugler W, Galimi F, Lee MS, Karin M: Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci USA 2006;103:16454–16459.
  55. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Eagle AR, Vats D, Brombacher F, Ferrante AW, Chawla A: Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 2007;447:1116–1120.
  56. Huber J, Loffler M, Bilban M, Reimers M, Kadl A, Todoric J, Zeyda M, Geyeregger R, Schreiner M, Weichhart T, Leitinger N, Waldhausl W, Stulnig TM: Prevention of high-fat diet-induced adipose tissue remodeling in obese diabetic mice by n–3 polyunsaturated fatty acids. Int J Obes (Lond) 2007;31:1004–1013.
  57. Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S, Gillum M, Shulman GI: Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-γ-dependent mechanism in mice. Diabetes 2006;55:924–928.
  58. Ye P, Zhang XJ, Wang ZJ, Zhang C: Effect of aging on the expression of peroxisome proliferator-activated receptor-γ and the possible relation to insulin resistance. Gerontology 2006;52:69–75.
  59. Stulnig TM: Immunomodulation by polyunsaturated fatty acids: mechanisms and effects. Int Arch Allergy Immunol 2003;132:310–321.
  60. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444:337–342.
  61. Guri AJ, Hontecillas R, Ferrer G, Casagran O, Wankhade U, Noble AM, Eizirik DL, Ortis F, Cnop M, Liu D, Si H, Bassaganya-Riera J: Loss of PPARγ in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue. J Nutr Biochem 2008;19:216–228.

 goto top of outline Author Contacts

Thomas M. Stulnig, MD
Department of Medicine III, Clinical Division of Endocrinology and Metabolism
Währinger Gürtel 18–20, AT–1090 Vienna (Austria)
Tel. +43 1 40400 4368, Fax +43 1 40400 7790
E-Mail thomas.stulnig@meduniwien.ac.at

 goto top of outline Article Information

Received: September 29, 2008
Accepted: November 17, 2008
Published online: April 8, 2009
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 0, Number of References : 61

 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 55, No. 4, Year 2009 (Cover Date: July 2009)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.