Endocrine Pathology

, Volume 25, Issue 1, pp 93–101 | Cite as

Morphological and Inflammatory Changes in Visceral Adipose Tissue During Obesity

  • Xavier S. Revelo
  • Helen Luck
  • Shawn Winer
  • Daniel A. Winer
Article

Abstract

Obesity is a major health burden worldwide and is a major factor in the development of insulin resistance and metabolic complications such as type II diabetes. Chronic nutrient excess leads to visceral adipose tissue (VAT) expansion and dysfunction in an active process that involves the adipocytes, their supporting matrix, and immune cell infiltrates. These changes contribute to adipose tissue hypoxia, adipocyte cell stress, and ultimately cell death. Accumulation of lymphocytes, macrophages, and other immune cells around dying adipocytes forms the so-called “crown-like structure”, a histological hallmark of VAT in obesity. Cross talk between immune cells in adipose tissue dictates the overall inflammatory response, ultimately leading to the production of pro-inflammatory mediators which directly induce insulin resistance in VAT. In this review, we summarize recent studies demonstrating the dramatic changes that occur in visceral adipose tissue during obesity leading to low-grade chronic inflammation and metabolic disease.

Keywords

Obesity Visceral adipose tissue Inflammation Immunology Diabetes 

References

  1. 1.
    Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser, 2000. 894: p. i–xii, 1–253.Google Scholar
  2. 2.
    Gualillo, O., Mediators of inflammation in obesity and its comorbidities. Mediators Inflamm, 2010. 2010.Google Scholar
  3. 3.
    Kahn, S.E., R.L. Hull, and K.M. Utzschneider, Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature, 2006. 444(7121): p. 840–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Khandekar, M.J., P. Cohen, and B.M. Spiegelman, Molecular mechanisms of cancer development in obesity. Nat Rev Cancer, 2011. 11(12): p. 886–95.PubMedCrossRefGoogle Scholar
  5. 5.
    Masuoka, H.C. and N. Chalasani, Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci, 2013. 1281: p. 106–22.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Rask-Madsen, C. and C.R. Kahn, Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol, 2012. 32(9): p. 2052–9.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Wild, S., et al., Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 2004. 27(5): p. 1047–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Wronska, A. and Z. Kmiec, Structural and biochemical characteristics of various white adipose tissue depots. Acta Physiol (Oxf), 2012. 205(2): p. 194–208.CrossRefGoogle Scholar
  9. 9.
    Khan, T., et al., Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol, 2009. 29(6): p. 1575–91.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Divoux, A. and K. Clement, Architecture and the extracellular matrix: the still unappreciated components of the adipose tissue. Obes Rev, 2011. 12(5): p. e494–503.PubMedCrossRefGoogle Scholar
  11. 11.
    Yarak, S. and O.K. Okamoto, Human adipose-derived stem cells: current challenges and clinical perspectives. An Bras Dermatol, 2010. 85(5): p. 647–56.PubMedCrossRefGoogle Scholar
  12. 12.
    Mortensen, S.B., et al., Membrane-tethered delta-like 1 homolog (DLK1) restricts adipose tissue size by inhibiting preadipocyte proliferation. Diabetes, 2012. 61(11): p. 2814–22.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Arner, P., Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab, 2005. 19(4): p. 471–82.PubMedCrossRefGoogle Scholar
  14. 14.
    Skurk, T., et al., Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab, 2007. 92(3): p. 1023–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Meyer, L.K., et al., Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity. Adipocyte, 2013. 2(4): p. 217–26.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Traustadottir, G.A., et al., Preadipocytes proliferate and differentiate under the guidance of Delta-like 1 homolog (DLK1). Adipocyte, 2013. 2(4): p. 272–5.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Spalding, K.L., et al., Dynamics of fat cell turnover in humans. Nature, 2008. 453(7196): p. 783–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Pasarica, M., et al., Adipose tissue collagen VI in obesity. J Clin Endocrinol Metab, 2009. 94(12): p. 5155–62.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Mariman, E.C. and P. Wang, Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci, 2010. 67(8): p. 1277–92.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Huang, G., et al., alpha3(V) collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues. J Clin Invest, 2011. 121(2): p. 769–83.Google Scholar
  21. 21.
    Szendroedi, J. and M. Roden, Ectopic lipids and organ function. Curr Opin Lipidol, 2009. 20(1): p. 50–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Sell, H. and J. Eckel, Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes. Curr Opin Clin Nutr Metab Care, 2010. 13(4): p. 366–70.PubMedCrossRefGoogle Scholar
  23. 23.
    Cao, Y., Angiogenesis modulates adipogenesis and obesity. J Clin Invest, 2007. 117(9): p. 2362–8.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Cao, Y., Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat Rev Drug Discov, 2010. 9(2): p. 107–15.PubMedGoogle Scholar
  25. 25.
    Brakenhielm, E., et al., Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res, 2004. 94(12): p. 1579–88.PubMedCrossRefGoogle Scholar
  26. 26.
    Barnhart, K.F., et al., A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci Transl Med, 2011. 3(108): p. 108ra112.Google Scholar
  27. 27.
    Hotamisligil, G.S., N.S. Shargill, and B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science, 1993. 259(5091): p. 87–91.PubMedCrossRefGoogle Scholar
  28. 28.
    Weisberg, S.P., et al., Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest, 2003. 112(12): p. 1796–808.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Xu, H., et al., Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest, 2003. 112(12): p. 1821–30.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Chawla, A., K.D. Nguyen, and Y.P. Goh, Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol, 2011. 11(11): p. 738–49.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Olefsky, J.M. and C.K. Glass, Macrophages, inflammation, and insulin resistance. Annu Rev Physiol, 2010. 72: p. 219–46.PubMedCrossRefGoogle Scholar
  32. 32.
    Mathis, D., Immunological goings-on in visceral adipose tissue. Cell Metab, 2013. 17(6): p. 851–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Osborn, O. and J.M. Olefsky, The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med, 2012. 18(3): p. 363–74.PubMedCrossRefGoogle Scholar
  34. 34.
    Liu, J., et al., Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med, 2009. 15(8): p. 940–5.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Elgazar-Carmon, V., et al., Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res, 2008. 49(9): p. 1894–903.PubMedCrossRefGoogle Scholar
  36. 36.
    Talukdar, S., et al., Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med, 2012.Google Scholar
  37. 37.
    Winer, S., et al., Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med, 2009. 15(8): p. 921–9.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Nishimura, S., et al., CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med, 2009. 15(8): p. 914–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Winer, D.A., et al., B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med, 2011. 17(5): p. 610–7.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Feuerer, M., et al., Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med, 2009. 15(8): p. 930–9.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Wu, D., et al., Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science, 2011. 332(6026): p. 243–7.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Molofsky, A.B.., et al., Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med, 2013. 210(3): p. 535–49.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Jenkins, S.J., et al., Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science, 2011. 332(6035): p. 1284–1288.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Jenkins, S.J., et al., IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. The Journal of Experimental Medicine, 2013.Google Scholar
  45. 45.
    Lumeng, C.N., J.L. Bodzin, and A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest, 2007. 117(1): p. 175–84.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Lumeng, C.N., et al., Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes, 2007. 56(1): p. 16–23.PubMedCrossRefGoogle Scholar
  47. 47.
    Odegaard, J.I., et al., Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature, 2007. 447(7148): p. 1116–20.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Kawakami, T., et al., Resident renal mononuclear phagocytes comprise five discrete populations with distinct phenotypes and functions. J Immunol, 2013. 191(6): p. 3358–72.PubMedCrossRefGoogle Scholar
  49. 49.
    Stienstra, R., et al., Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J Biol Chem, 2008. 283(33): p. 22620–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Satoh, T., et al., Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature, 2013. 495(7442): p. 524–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Aouadi, M., et al., Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc Natl Acad Sci U S A, 2013. 110(20): p. 8278–83.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Han, M.S., et al., JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science, 2013. 339(6116): p. 218–22.PubMedCrossRefGoogle Scholar
  53. 53.
    Brinkmann, V., et al., Neutrophil extracellular traps kill bacteria. Science, 2004. 303(5663): p. 1532–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Yang, H., et al., Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J Immunol, 2010. 185(3): p. 1836–45.PubMedCrossRefGoogle Scholar
  55. 55.
    Strissel, K.J., et al., T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring), 2010. 18(10): p. 1918–25.CrossRefGoogle Scholar
  56. 56.
    McGillicuddy, F.C., et al., Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem, 2009. 284(46): p. 31936–44.Google Scholar
  57. 57.
    Dobrian, A.D., et al., Signal transducer and activator of transcription (STAT) 4 deficiency reduces obesity induced insulin resistance and adipose tissue inflammation. Diabetes, 2013.Google Scholar
  58. 58.
    Morris, D.L., et al., Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes, 2013. 62(8): p. 2762–72.PubMedCrossRefGoogle Scholar
  59. 59.
    Duffaut, C., et al., Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem Biophys Res Commun, 2009. 384(4): p. 482–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Jagannathan, M., et al., Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia, 2010. 53(7): p. 1461–71.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    DeFuria, J., et al., B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A, 2013. 110(13): p. 5133–8.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Cipolletta, D., et al., Tissular T(regs): a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin Immunol, 2011. 23(6): p. 431–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Tiemessen, M.M., et al., CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A, 2007. 104(49): p. 19446–51.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Ilan, Y., et al., Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proceedings of the National Academy of Sciences, 2010. 107(21): p. 9765–9770.CrossRefGoogle Scholar
  65. 65.
    Cipolletta, D., et al., PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 2012. 486(7404): p. 549–53.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Priceman, S.J., et al., Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A, 2013. 110(32): p. 13079–84.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Nishimura, S., et al., Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell metabolism, 2013.Google Scholar
  68. 68.
    Rossjohn, J., et al., Recognition of CD1d-restricted antigens by natural killer T cells. Nat Rev Immunol, 2012. 12(12): p. 845–57.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Ji, Y., et al., Activation of natural killer T cells promotes M2 Macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J Biol Chem, 2012. 287(17): p. 13561–71.Google Scholar
  70. 70.
    Schipper, H.S., et al., Natural killer T cells in adipose tissue prevent insulin resistance. J Clin Invest, 2012. 122(9): p. 3343–54.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Lynch, L., et al., Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity, 2012. 37(3): p. 574–87.PubMedCrossRefGoogle Scholar
  72. 72.
    Subramanian, S., et al., Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice. J Lipid Res, 2013. 54(10): p. 2831–41.PubMedCrossRefGoogle Scholar
  73. 73.
    Wu, L., et al., Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc Natl Acad Sci U S A, 2012. 109(19): p. E1143–52.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Lynch, L., et al., Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity. Eur J Immunol, 2009. 39(7): p. 1893–901.PubMedCrossRefGoogle Scholar
  75. 75.
    Mallevaey, T. and T. Selvanantham, Strategy of lipid recognition by invariant natural killer T cells: ‘one for all and all for one’. Immunology, 2012. 136(3): p. 273–82.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Elinav, E., et al., Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping. J Pathol, 2006. 209(1): p. 121–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Mantell, B.S., et al., Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS One, 2011. 6(6): p. e19831.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Kotas, M.E., et al., Impact of CD1d deficiency on metabolism. PLoS One, 2011. 6(9): p. e25478.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Satoh, M., et al., Type II NKT cells stimulate diet-induced obesity by mediating adipose tissue inflammation, steatohepatitis and insulin resistance. PLoS One, 2012. 7(2): p. e30568.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Ji, Y., et al., Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4. J Biol Chem, 2012. 287(29): p. 24378–86.Google Scholar
  81. 81.
    Wu, L. and L. Van Kaer, Contribution of lipid-reactive natural killer T cells to obesity-associated inflammation and insulin resistance. Adipocyte, 2013. 2(1): p. 12–16.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Cinti, S., et al., Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. Journal of Lipid Research, 2005. 46(11): p. 2347–2355.PubMedCrossRefGoogle Scholar
  83. 83.
    Prieur, X., et al., Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes, 2011. 60(3): p. 797–809.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Shapiro, H., et al., Adipose tissue foam cells are present in human obesity. J Clin Endocrinol Metab, 2013. 98(3): p. 1173–81.PubMedCrossRefGoogle Scholar
  85. 85.
    Strissel, K.J., et al., Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes, 2007. 56(12): p. 2910–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Giordano, A., et al., Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res, 2013. 54(9): p. 2423–36.PubMedCrossRefGoogle Scholar
  87. 87.
    Murano, I., et al., Time course of histomorphological changes in adipose tissue upon acute lipoatrophy. Nutr Metab Cardiovasc Dis, 2013. 23(8): p. 723–31.PubMedCrossRefGoogle Scholar
  88. 88.
    Miao, E.A., et al., Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol, 2010. 11(12): p. 1136–1142.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Galluzzi, L., et al., Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ, 2012. 19(1): p. 107–20.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Hosogai, N., et al., Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes, 2007. 56(4): p. 901–11.PubMedCrossRefGoogle Scholar
  91. 91.
    Ye, J., et al., 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, 2007. 293(4): p. E1118–28.PubMedCrossRefGoogle Scholar
  92. 92.
    Rausch, M.E., et al., Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond), 2008. 32(3): p. 451–63.CrossRefGoogle Scholar
  93. 93.
    Goossens, G.H., et al., Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation, 2011. 124(1): p. 67–76.PubMedCrossRefGoogle Scholar
  94. 94.
    Blaak, E.E., et al., β-adrenergic stimulation and abdominal subcutaneous fat blood flow in lean, obese, and reduced-obese subjects. Metabolism, 1995. 44(2): p. 183–187.PubMedCrossRefGoogle Scholar
  95. 95.
    Trayhurn, P., Hypoxia and adipose tissue function and dysfunction in obesity. Physiological Reviews, 2013. 93(1): p. 1–21.PubMedCrossRefGoogle Scholar
  96. 96.
    Pasarica, M., et al., Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes, 2009. 58(3): p. 718–725.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Yamauchi, T., et al., The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med, 2001. 7(8): p. 941–6.PubMedCrossRefGoogle Scholar
  98. 98.
    Boden, G., et al., Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes, 2008. 57(9): p. 2438–44.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Gregor, M.F., et al., Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes, 2009. 58(3): p. 693–700.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Chen, B., et al., Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun, 2006. 341(2): p. 549–56.PubMedCrossRefGoogle Scholar
  101. 101.
    Lolmede, K., et al., Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord, 2003. 27(10): p. 1187–95.PubMedCrossRefGoogle Scholar
  102. 102.
    Wang, G.L. and G.L. Semenza, General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A, 1993. 90(9): p. 4304–8.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Jiang, C., et al., Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes, 2011. 60(10): p. 2484–2495.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Odegaard, J.I. and A. Chawla, Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science, 2013. 339(6116): p. 172–7.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Trayhurn, P., Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev, 2013. 93(1): p. 1–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Xavier S. Revelo
    • 1
  • Helen Luck
    • 1
    • 4
  • Shawn Winer
    • 1
    • 2
  • Daniel A. Winer
    • 1
    • 2
    • 3
    • 4
    • 5
    • 6
  1. 1.Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI)University Health NetworkTorontoCanada
  2. 2.Department of PathologyUniversity Health NetworkTorontoCanada
  3. 3.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  4. 4.Department of ImmunologyUniversity of TorontoTorontoCanada
  5. 5.Department of EndocrinologyUniversity of TorontoTorontoCanada
  6. 6.MaRS Centre 10-352, Toronto Medical Discovery TowerTorontoCanada

Personalised recommendations