Inflammation and Adipose Dysfunction

  • Rachana Shah
  • Muredach P. Reilly


While inflammatory changes in obesity have been recognized for many years, the pathophysiology underlying these alterations is still being elucidated. In fact, the primarycausal mechanisms by which obesity results in activation of immune pathways are not yet fully understood. Some of the prominent theories are explored here.


Insulin Resistance Adipose Tissue Insulin Signaling Obese Mouse Adipose Tissue Inflammation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



R.S. is supported by a K12 award from the University of Pennsylvania Clinical and Translational Science Award (UL1RR024134) from the National Center for Research Resources (NCRR). R.S. and M.P.R. receive support from the Diabetes and Endocrine Research Center (P30-DK 019525) at the University of Pennsylvania. M.P.R. is supported by RO1-DK071224 and P50 HL-083799-SCCOR from the National Institutes of Health.


  1. 1.
    Buren, J. & Eriksson, J. W. (2005). Is insulin resistance caused by defects in insulin’s target cells or by a stressed mind? Diabetes/Metabolism Research and Reviews, 21(6), 487–494.CrossRefPubMedGoogle Scholar
  2. 2.
    Valsamakis, G., Anwar, A., Tomlinson, J. W., et al. (2004). 11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. The Journal of Clinical Endocrinology and Metabolism, 89(9). 4755–4761.CrossRefPubMedGoogle Scholar
  3. 3.
    Kotelevtsev, Y., Holmes, M. C., Burchell, A., et al. (1997). 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proceedings of the National Academy of Sciences of the United States of America, 94(26), 14924–14929.CrossRefPubMedGoogle Scholar
  4. 4.
    Agwunobi, A. O., Reid, C., Maycock, P., Little, R. A., & Carlson, G. L. (2000). Insulin resistance and substrate utilization in human endotoxemia. The Journal of Clinical Endocrinology and Metabolism, 85(10), 3770–3778.CrossRefPubMedGoogle Scholar
  5. 5.
    Mehta NN, McGillicuddy FC, Anderson PD, et al. Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans. /Diabetes./ 2010 59(1):172–81.Google Scholar
  6. 6.
    Shah, R., Lu, Y., Hinkle, C. C., et al. (2009). Gene profiling of human adipose tissue during evoked inflammation in vivo. Diabetes, 58(10), 2211–2219.CrossRefPubMedGoogle Scholar
  7. 7.
    Backhed, F., Manchester, J. K., Semenkovich, C. F., & Gordon, J. I. (2007). Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the United States of America, 104(3), 979–984.CrossRefPubMedGoogle Scholar
  8. 8.
    Ghanim, H., Abuaysheh, S., Sia, C. L., et al. (2009). Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in ­mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care, 32(12), 2281–2287.CrossRefPubMedGoogle Scholar
  9. 9.
    Song, M. J., Kim, K. H., Yoon, J. M., Kim, J. B. (2006). Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochemical and Biophysical Research Communications, 346(3), 739–745.CrossRefPubMedGoogle Scholar
  10. 10.
    Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W., Jr. (2003). Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation, 112(12), 1796–1808.PubMedGoogle Scholar
  11. 11.
    Spalding, K. L., Arner, E., Westermark, P. O., et al. (2008). Dynamics of fat cell turnover in humans. Nature, 453(7196), 783–787.CrossRefPubMedGoogle Scholar
  12. 12.
    Larson-Meyer, D. E., Heilbronn, L. K., Redman, L. M., et al. (2006). Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care, 29(6), 1337–1344.CrossRefPubMedGoogle Scholar
  13. 13.
    Yin, J., Gao, Z., He, Q., Zhou, D., Guo, Z., & Ye, J. (2009). Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. American Journal of Physiology. Endocrinology and Metabolism, 296(2), E333–342.CrossRefPubMedGoogle Scholar
  14. 14.
    Hosogai, N., Fukuhara, A., Oshima, K., et al. (2007). Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes, 56(4), 901–911.CrossRefPubMedGoogle Scholar
  15. 15.
    Cancello, R., Henegar, C., Viguerie, N., et al. (2005). Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes, 54(8), 2277–2286.CrossRefPubMedGoogle Scholar
  16. 16.
    Bluher, M. (2009). Adipose tissue dysfunction in obesity. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 117(6), 241–250.Google Scholar
  17. 17.
    Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006). TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of Clinical Investigation, 116(11), 3015–3025.CrossRefPubMedGoogle Scholar
  18. 18.
    Kintscher, U., Hartge, M., Hess, K., et al. (2008). T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(7), 1304–1310.CrossRefPubMedGoogle Scholar
  19. 19.
    Lumeng, C. N., Deyoung, S. M., Bodzin, J. L., & Saltiel, A. R. (2007). Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes, 56(1), 16–23.CrossRefPubMedGoogle Scholar
  20. 20.
    Verschuren, L., Kooistra, T., Bernhagen, J., et al. (2009). MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease. Circulation Research, 105(1), 99–107.CrossRefPubMedGoogle Scholar
  21. 21.
    Yeop Han C, Kargi AY, Omer M, et al. Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: dissociation of adipocyte hypertrophy from inflammation. /Diabetes. /2010;59(2):386–96.Google Scholar
  22. 22.
    Cinti, S., Mitchell, G., Barbatelli, G., et al. (2005). Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. Journal of Lipid Research, 46(11), 2347–2355.CrossRefPubMedGoogle Scholar
  23. 23.
    Permana, P. A., Menge, C., & Reaven, P. D. (2006). Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochemical and Biophysical Research Communications, 341(2), 507–514.CrossRefPubMedGoogle Scholar
  24. 24.
    Inouye, K. E., Shi, H., Howard, J. K., et al. (2007). Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes, 56(9), 2242–2250.CrossRefPubMedGoogle Scholar
  25. 25.
    Ortega Martinez de Victoria, E., Xu, X., Koska, J., et al. (2009). Macrophage content in subcutaneous adipose tissue: associations with adiposity, age, inflammatory markers, and whole-body insulin action in healthy Pima Indians. Diabetes, 58(2), 385–393.CrossRefPubMedGoogle Scholar
  26. 26.
    Capel, F., Klimcakova, E., Viguerie, N., et al. (2009). Macrophages and adipocytes in human obesity: adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization. Diabetes, 58(7), 1558–1567.CrossRefPubMedGoogle Scholar
  27. 27.
    Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., & Locati, M. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends in Immunology, 25(12), 677–686.CrossRefPubMedGoogle Scholar
  28. 28.
    Lumeng, C. N., Bodzin, J. L., & Saltiel, A. R. (2007). Obesity induces a phenotypic switch in adipose tissue macrophage polarization. The Journal of Clinical Investigation, 117(1), 175–184.CrossRefPubMedGoogle Scholar
  29. 29.
    Fujisaka, S., Usui, I., Bukhari, A., et al. (2009). Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes, 58(11), 2574–2582.CrossRefPubMedGoogle Scholar
  30. 30.
    Weisberg, S. P., Hunter, D., Huber, R., et al. (2006). CCR2 modulates inflammatory and metabolic effects of high-fat feeding. The Journal of Clinical Investigation, 116(1), 115–124.CrossRefPubMedGoogle Scholar
  31. 31.
    Aron-Wisnewsky, J., Tordjman, J., Poitou, C., et al. (2009). Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. The Journal of Clinical Endocrinology and Metabolism, 94(11), 4619–4623.CrossRefPubMedGoogle Scholar
  32. 32.
    Alexander, W. S. (2002). Suppressors of cytokine signalling (SOCS) in the immune system. Nature Reviews. Immunology, 2(6), 410–416.PubMedGoogle Scholar
  33. 33.
    Wu, H., Ghosh, S., Perrard, X. D., et al. (2007). T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation, 115(8), 1029–1038.CrossRefPubMedGoogle Scholar
  34. 34.
    Rocha, V. Z., Folco, E. J., Sukhova, G., et al. (2008). Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circulation Research, 103(5), 467–476.CrossRefPubMedGoogle Scholar
  35. 35.
    Lumeng, C. N., Maillard, I., & Saltiel, A. R. (2009). T-ing up inflammation in fat. Nature Medicine, 15(8), 846–847.CrossRefPubMedGoogle Scholar
  36. 36.
    McGillicuddy, F. C., Chiquoine, E. H., Hinkle, C. C., et al. (2009). Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. The Journal of Biological Chemistry, 284(46), 31936–31944.CrossRefPubMedGoogle Scholar
  37. 37.
    Feuerer, M., Herrero, L., Cipolletta, D., et al. (2009). Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Medicine, 15(8), 930–939.CrossRefPubMedGoogle Scholar
  38. 38.
    Winer, S., Chan, Y., Paltser, G., et al. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature Medicine, 15(8), 921–929.CrossRefPubMedGoogle Scholar
  39. 39.
    Nishimura, S., Manabe, I., Nagasaki, M., et al. (2009). CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine, 15(8), 914–920.CrossRefPubMedGoogle Scholar
  40. 40.
    Duffaut, C., Zakaroff-Girard, A., Bourlier, V., et al. (2009). Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(10), 1608–1614.CrossRefPubMedGoogle Scholar
  41. 41.
    Shin, J. H., Shin, D. W., & Noh, M. (2009). Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes. Biochemical Pharmacology, 77(12), 1835–1844.CrossRefPubMedGoogle Scholar
  42. 42.
    Cani, P. D., Amar, J., Iglesias, M. A., et al. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 56(7), 1761–1772.CrossRefPubMedGoogle Scholar
  43. 43.
    Shah, A., Mehta, N., & Reilly, M. P. (2008). Adipose inflammation, insulin resistance, and cardiovascular disease. JPEN. Journal of Parenteral and Enteral Nutrition, 32(6), 638–644.CrossRefPubMedGoogle Scholar
  44. 44.
    Mohamed-Ali, V., Goodrick, S., Rawesh, A., et al. (1997). Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. The Journal of Clinical Endocrinology and Metabolism, 82(12), 4196–4200.CrossRefPubMedGoogle Scholar
  45. 45.
    Jager, J., Gremeaux, T., Cormont, M., Le Marchand-Brustel, Y., Tanti, J. F. (2007). Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology, 148(1), 241–251.CrossRefPubMedGoogle Scholar
  46. 46.
    Garcia, M. C., Wernstedt, I., Berndtsson, A., et al. (2006). Mature-onset obesity in interleukin-1 receptor I knockout mice. Diabetes, 55(5), 1205–1213.CrossRefPubMedGoogle Scholar
  47. 47.
    Somm, E., Henrichot, E., Pernin, A., et al. (2005). Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure. Diabetes, 54(12), 3503–3509.CrossRefPubMedGoogle Scholar
  48. 48.
    Juge-Aubry, C. E., Somm, E., Giusti, V., et al. (2003). Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. Diabetes, 52(5), 1104–1110.CrossRefPubMedGoogle Scholar
  49. 49.
    Dahlman, I., Kaaman, M., Olsson, T., et al. (2005). A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects. The Journal of Clinical Endocrinology and Metabolism, 90(10), 5834–5840.CrossRefPubMedGoogle Scholar
  50. 50.
    Sell, H., & Eckel, J. (2009). Chemotactic cytokines, obesity and type 2 diabetes: in vivo and in vitro evidence for a possible causal correlation? The Proceedings of the Nutrition Society, 68(4), 378–384.CrossRefPubMedGoogle Scholar
  51. 51.
    Straczkowski, M., Dzienis-Straczkowska, S., Stepien, A., Kowalska, I., Szelachowska, M., & Kinalska, I. (2002), Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. The Journal of Clinical Endocrinology and Metabolism, 87(10), 4602–4606.CrossRefPubMedGoogle Scholar
  52. 52.
    Bost, F., Aouadi, M., Caron, L., et al. (2005). The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes, 54(2), 402–411.CrossRefPubMedGoogle Scholar
  53. 53.
    Carlson, C. J., & Rondinone, C. M. (2005). Pharmacological inhibition of p38 MAP kinase results in improved glucose uptake in insulin-resistant 3T3-L1 adipocytes. Metabolism: Clinical and Experimental, 54(7), 895–901.Google Scholar
  54. 54.
    Um, S. H., Frigerio, F., Watanabe, M., et al. (2004). Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature, 431(7005), 200–205.CrossRefPubMedGoogle Scholar
  55. 55.
    Lehrke, M., & Lazar, M. A. (2005). The many faces of PPARgamma. Cell, 123(6), 993–999.CrossRefPubMedGoogle Scholar
  56. 56.
    Schulz, T. J., & Tseng, Y. H. (2009). Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine & Growth Factor Reviews, 20(5–6), 523–531.CrossRefGoogle Scholar
  57. 57.
    Lefterova, M. I., & Lazar, M. A. (2009). New developments in adipogenesis. Trends in Endocrinology and Metabolism: TEM, 20(3), 107–114.CrossRefPubMedGoogle Scholar
  58. 58.
    Baranova, A., Collantes, R., Gowder, S. J., et al. (2005). Obesity-related differential gene expression in the visceral adipose tissue. Obesity Surgery: The Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand, 15(6), 758–765.Google Scholar
  59. 59.
    Gomez-Ambrosi, J., Catalan, V., Diez-Caballero, A., et al. (2004). Gene expression profile of omental adipose tissue in human obesity. The FASEB Journal: Offical Publication of the Federation of American Societies for Experimental Biology, 18(1), 215–217.Google Scholar
  60. 60.
    Nair, S., Lee, Y. H., Rousseau, E., et al. (2005). Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with non-obese Pima Indians. Diabetologia, 48(9), 1784–1788.CrossRefPubMedGoogle Scholar
  61. 61.
    Alvarez-Llamas, G., Szalowska, E., de Vries, M. P., et al. (2007). Characterization of the human visceral adipose tissue secretome. Molecular & Cellular Proteomics: MCP, 6(4), 589–600.CrossRefGoogle Scholar
  62. 62.
    Zvonic, S., Lefevre, M., Kilroy, G., et al. (2007). Secretome of primary cultures of human adipose-derived stem cells: modulation of serpins by adipogenesis. Molecular & Cellular Proteomics: MCP, 6(1), 18–28.CrossRefPubMedGoogle Scholar
  63. 63.
    Forsythe, L. K., Wallace, J. M., & Livingstone, M. B. (2008). Obesity and inflammation: the effects of weight loss. Nutrition Research Review, 21(2), 117–133.CrossRefGoogle Scholar
  64. 64.
    Kolak, M., Yki-Jarvinen, H., Kannisto, K., et al. (2007). Effects of chronic rosiglitazone therapy on gene expression in human adipose tissue in vivo in patients with type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism, 92(2), 720–724.CrossRefPubMedGoogle Scholar
  65. 65.
    Larsen, C. M., Faulenbach, M., Vaag, A., Ehses, J. A., Donath, M. Y., & Mandrup-Poulsen, T. (2009). Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care, 32(9), 1663–1668.CrossRefPubMedGoogle Scholar
  66. 66.
    Hundal, R. S., Petersen, K. F., Mayerson, A. B., et al. (2002). Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. The Journal of Clinical Investigation, 109(10), 1321–1326.PubMedGoogle Scholar
  67. 67.
    Goldfine, A. B., Silver, R., Aldhahi, W., et al. (2008). Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clinical and Translational Science, 1(1), 36–43.CrossRefPubMedGoogle Scholar
  68. 68.
    Fleischman, A., Shoelson, S. E., Bernier, R., & Goldfine, A. B. (2008). Salsalate improves ­glycemia and inflammatory parameters in obese young adults. Diabetes Care, 31(2), 289–294.CrossRefPubMedGoogle Scholar
  69. 69.
    Cani, P. D., Bibiloni, R., Knauf, C., et al. (2008). Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes, 57(6), 1470–1481.CrossRefPubMedGoogle Scholar
  70. 70.
    Patsouris, D., Li, P. P., Thapar, D., Chapman, J., Olefsky, J. M., & Neels, J. G. (2008). Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metabolism, 8(4), 301–309.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Cardiovascular Institute and the Institute for Diabetes, Obesity and Metabolism, and the Institute for Translational Medicine and Therapeutics, Departments of Medicine and PharmacologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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