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  • Review Article
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Adipocytokines: mediators linking adipose tissue, inflammation and immunity

Nature Reviews Immunology volume 6, pages 772–783 (2006)Cite this article

Key Points

  • Insulin resistance, most commonly in the context of obesity, is the main risk factor for type 2 diabetes mellitus and cardiovascular diseases.

  • Several pro-inflammatory cytokines (such as tumour-necrosis factor and interleukin-6), signalling proteins and endoplasmic-reticulum stress are associated with the development of insulin resistance.

  • Adipose tissue is the largest endocrine organ in humans and releases large amounts of adipocytokines — mediators that are mainly, but not exclusively, synthesized by adipocytes in white adipose tissue. Adiponectin and leptin are the two most abundant adipocytokines.

  • Adipose tissue contributes to the development of insulin resistance, not only by the synthesis of adipocytokines, but also by the production of many other pro-inflammatory mediators.

  • Obesity is associated with increased macrophage infiltration of adipose tissue, and these macrophages might contribute to the chronic inflammatory response that is observed in obesity and insulin resistance.

  • Adiponectin is synthesized mainly by adipocytes. It suppresses macrophage functions and inflammatory processes throughout the body, and decreases insulin resistance.

  • Leptin, an adipocytokine that was identified more than a decade ago, links nutritional status with neuroendocrine and immune functions. In contrast to adiponectin, serum levels of leptin are increased in people who are obese and this adipocytokine has several pro-inflammatory properties.

  • Resistin, another pro-inflammatory adipocytokine, seems to have different functions in mice and humans. It is potentially involved in the regulation of insulin resistance and has many pro-inflammatory functions.

  • Visfatin mimics insulin functions and thereby decreases insulin resistance. Its initial identification as pre-B-cell colony-enhancing factor (PBEF) indicates that it has an important role in inflammatory processes, again supporting the close relationship between inflammation and insulin resistance.

Abstract

There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.

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Figure 1: Adipose tissue: cellular components and molecules synthesized.
Figure 2: Adiponectin: sources, structure and effects on pro- and anti-inflammatory cytokines.
Figure 3: Effects of various adipocytokines on the monocyte–macrophage system.
Figure 4: Effects of adipocytokines on adaptive immunity.

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References

  1. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer 4, 579–591 (2004).

    Article  CAS  Google Scholar 

  3. Mannino, D. M. et al. Boys with high body masses have an increased risk of developing asthma: findings from the National Longitudinal Survey of Youth (NLSY). Int. J. Obesity (Lond) 30, 6–13 (2006).

    Article  CAS  Google Scholar 

  4. La Cava, A. & Matarese, G. The weight of leptin in immunity. Nature Rev. Immunol. 4, 371–379 (2004).

    Article  CAS  Google Scholar 

  5. Kusminski, C. M., McTernan, P. G. & Kumar, S. Role of resistin in obesity, insulin resistance and Type II diabetes. Clin. Sci. (Lond) 109, 243–256 (2005).

    Article  CAS  Google Scholar 

  6. Weisberg, S. P. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115–124 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fantuzzi, G. Adipose tissue, adipokines, and inflammation. J. Allergy Clin. Immunol. 115, 911–919 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Kern, P. A. et al. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 95, 2111–2119 (1995). This study (together with reference 9) shows for the first time that the pro-inflammatory cytokine TNF is a mediator of insulin resistance in obesity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKKβ. Science 293, 1673–1677 (2001). The authors describe a central role for IKKβ in the pathogenesis of insulin resistance.

    Article  CAS  PubMed  Google Scholar 

  15. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002). This is the first report that JNK is a mediator of obesity and insulin resistance.

    Article  CAS  PubMed  Google Scholar 

  16. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Rui, L., Yuan, M., Frantz, D., Shoelson, S. & White, M. F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277, 42394–42398 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Croker, B. A. et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nature Immunol. 4, 540–545 (2003).

    Article  CAS  Google Scholar 

  19. Arkan, M. C. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nature Med. 11, 191–198 (2005). This paper provides evidence that myeloid cells (macrophages) regulate systemic insulin resistance in an IKKβ-dependent manner.

    Article  CAS  PubMed  Google Scholar 

  20. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nature Med. 11, 183–190 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Pineiro, R. et al. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett. 579, 5163–5169 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Delaigle, A. M., Jonas, J. C., Bauche, I. B., Cornu, O. & Brichard, S. M. Induction of adiponectin in skeletal muscle by inflammatory cytokines: in vivo and in vitro studies. Endocrinology 145, 5589–5597 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Wolf, A. M. et al. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J. Hepatol. 44, 537–543 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Maeda, K. et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem. Biophys. Res. Commun. 221, 286–289 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Hu, E., Liang, P. & Spiegelman, B. M. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 271, 10697–10703 (1996). References 24–26 report the cloning and identification of adiponectin in mice and humans.

    Article  CAS  PubMed  Google Scholar 

  27. Waki, H. et al. Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1. Endocrinology 146, 790–796 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Waki, H. et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J. Biol. Chem. 278, 40352–40363 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Fisher, F. F. et al. Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia 48, 1084–1087 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Pajvani, U. B. et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J. Biol. Chem. 279, 12152–12162 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Bobbert, T. et al. Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes 54, 2712–2719 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Yamauchi, T. et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769 (2003). This is the first report of the isolation and characterization of adiponectin receptors 1 and 2.

    Article  CAS  PubMed  Google Scholar 

  34. Hug, C. et al. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc. Natl Acad. Sci. USA 101, 10308–10313 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Maeda, N. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nature Med. 8, 731–737 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Fasshauer, M. et al. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun. 301, 1045–1050 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Bruun, J. M. et al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am. J. Physiol. Endocrinol. Metab. 285, E527–E533 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Maeda, N. et al. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50, 2094–2099 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Iwaki, M. et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52, 1655–1663 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Ouchi, N. et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100, 2473–2476 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Yokota, T. et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96, 1723–1732 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Wolf, A. M., Wolf, D., Rumpold, H., Enrich, B. & Tilg, H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem. Biophys. Res. Commun. 323, 630–635 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Yamaguchi, N. et al. Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS Lett. 579, 6821–6826 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Saijo, S., Nagata, K., Nakano, Y., Tobe, T. & Kobayashi, Y. Inhibition by adiponectin of IL-8 production by human macrophages upon coculturing with late apoptotic cells. Biochem. Biophys. Res. Commun. 334, 1180–1183 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Neumeier, M. et al. Different effects of adiponectin isoforms in human monocytic cells. J. Leukocyte Biol. 79, 803–808 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Berg, A. H., Combs, T. P. & Scherer, P. E. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol. Metab. 13, 84–89 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Nawrocki, A. R. et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor-γ agonists. J. Biol. Chem. 281, 2654–2660 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Shklyaev, S. et al. Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc. Natl Acad. Sci. USA 100, 14217–14222 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xu, A. et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Invest. 112, 91–100 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kamada, Y. et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 125, 1796–1807 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Masaki, T. et al. Adiponectin protects LPS-induced liver injury through modulation of TNF-α in KK-Ay obese mice. Hepatology 40, 177–184 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Sennello, J. A. et al. Regulation of T cell-mediated hepatic inflammation by adiponectin and leptin. Endocrinology 146, 2157–2164 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Kahn, B. B., Alquier, T., Carling, D. & Hardie, D. G. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15–25 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Med. 8, 1288–1295 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Shibata, R. et al. Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of AMP-activated protein kinase signaling. J. Biol. Chem. 279, 28670–28674 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Shibata, R. et al. Adiponectin protects against myocardial ischemia–reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nature Med. 11, 1096–1103 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Kubota, N. et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J. Biol. Chem. 277, 25863–25866 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Okamoto, Y. et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106, 2767–2770 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Kawano, T. et al. Close association of hypoadiponectinemia with arteriosclerosis obliterans and ischemic heart disease. Metabolism 54, 653–656 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Maahs, D. M. et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation 111, 747–753 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Iglseder, B. et al. Plasma adiponectin levels and sonographic phenotypes of subclinical carotid artery atherosclerosis: data from the SAPHIR Study. Stroke 36, 2577–2582 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Mandel, M. A. & Mahmoud, A. A. Impairment of cell-mediated immunity in mutation diabetic mice (db/db). J. Immunol. 120, 1375–1377 (1978).

    CAS  PubMed  Google Scholar 

  63. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). This study reports the cloning of the gene encoding leptin in mice and humans.

    Article  CAS  PubMed  Google Scholar 

  64. Lord, G. M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998). The authors show for the first time that leptin modulates CD4+ T-cell responses.

    Article  CAS  PubMed  Google Scholar 

  65. Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Grunfeld, C. et al. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J. Clin. Invest. 97, 2152–2157 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sarraf, P. et al. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J. Exp. Med. 185, 171–175 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gainsford, T. et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc. Natl Acad. Sci. USA 93, 14564–14568 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Aleffi, S. et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology 42, 1339–1348 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Matarese, G., Moschos, S. & Mantzoros, C. S. Leptin in immunology. J. Immunol. 174, 3137–3142 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Zhao, T. et al. Globular adiponectin decreases leptin-induced tumor necrosis factor-α expression by murine macrophages: involvement of cAMP-PKA and MAPK pathways. Cell Immunol. 238, 19–30 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Tian, Z., Sun, R., Wei, H. & Gao, B. Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation. Biochem. Biophys. Res. Commun. 298, 297–302 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Howard, J. K. et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104, 1051–1059 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Takahashi, N., Waelput, W. & Guisez, Y. Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor. J. Exp. Med. 189, 207–212 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Faggioni, R. et al. Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor-α and IL-18. Proc. Natl Acad. Sci. USA 97, 2367–2372 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Siegmund, B., Lear-Kaul, K. C., Faggioni, R. & Fantuzzi, G. Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis. Eur. J. Immunol. 32, 552–560 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Matarese, G. et al. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J. Immunol. 166, 5909–5916 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Siegmund, B. et al. Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice. Gut 53, 965–972 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Holcomb, I. N. et al. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19, 4046–4055 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001). This study (together with references 79 and 81) reports the cloning and identification of resistin, a thiazolidinedione-regulated, adipocyte-derived protein that mediates insulin resistance in mice.

    Article  CAS  PubMed  Google Scholar 

  81. Kim, K. H., Lee, K., Moon, Y. S. & Sul, H. S. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J. Biol. Chem. 276, 11252–11256 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Patel, S. D., Rajala, M. W., Rossetti, L., Scherer, P. E. & Shapiro, L. Disulfide-dependent multimeric assembly of resistin family hormones. Science 304, 1154–1158 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Kaser, S. et al. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem. Biophys. Res. Commun. 309, 286–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Lehrke, M. et al. An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med. 1, e45 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Bajaj, M., Suraamornkul, S., Hardies, L. J., Pratipanawatr, T. & DeFronzo, R. A. Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients. Int. J. Obes. Relat. Metab. Disord. 28, 783–789 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Bokarewa, M., Nagaev, I., Dahlberg, L., Smith, U. & Tarkowski, A. Resistin, an adipokine with potent proinflammatory properties. J. Immunol. 174, 5789–5795 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Silswal, N. et al. Human resistin stimulates the pro-inflammatory cytokines TNF-α and IL-12 in macrophages by NF-κB-dependent pathway. Biochem. Biophys. Res. Commun. 334, 1092–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Verma, S. et al. Resistin promotes endothelial cell activation: further evidence of adipokine–endothelial interaction. Circulation 108, 736–740 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Savage, D. B. et al. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-γ action in humans. Diabetes 50, 2199–2202 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. McTernan, C. L. et al. Resistin, central obesity, and type 2 diabetes. Lancet 359, 46–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Utzschneider, K. M. et al. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia 48, 2330–2333 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Jung, H. S. et al. Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc. Res. 69, 76–85 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Kawanami, D. et al. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine–endothelial cell interactions. Biochem. Biophys. Res. Commun. 314, 415–419 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Axelsson, J. et al. Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance. Kidney Int. 69, 596–604 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Fukuhara, A. et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307, 426–430 (2005). This study identifies visfatin as a new adipocytokine that is preferentially expressed in visceral fat and that mimics insulin activity by binding and activating the insulin receptor.

    Article  CAS  PubMed  Google Scholar 

  96. Samal, B. et al. Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol. Cell Biol. 14, 1431–1437 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Ye, S. Q. et al. Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. Am. J. Respir. Crit. Care Med. 171, 361–370 (2005).

    Article  PubMed  Google Scholar 

  98. Jia, S. H. et al. Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. J. Clin. Invest. 113, 1318–1327 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hida, K. et al. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc. Natl Acad. Sci. USA 102, 10610–10615 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Wang, Y. et al. Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J. Biol. Chem. 280, 18341–18347 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Brakenhielm, E. et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc. Natl Acad. Sci. USA 101, 2476–2481 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bub, J. D., Miyazaki, T. & Iwamoto, Y. Adiponectin as a growth inhibitor in prostate cancer cells. Biochem. Biophys. Res. Commun. 340, 1158–1166 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Garofalo, C. & Surmacz, E. Leptin and cancer. J. Cell. Physiol. 207, 12–22 (2005).

    Article  CAS  Google Scholar 

  105. Ishikawa, M. et al. Plasma adiponectin and gastric cancer. Clin. Cancer Res. 11, 466–472 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Miyoshi, Y. et al. Association of serum adiponectin levels with breast cancer risk. Clin. Cancer Res. 9, 5699–5704 (2003).

    CAS  PubMed  Google Scholar 

  107. Petridou, E. et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case–control study in Greece. J. Clin. Endocrinol. Metab. 88, 993–997 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Goktas, S. et al. Prostate cancer and adiponectin. Urology 65, 1168–1172 (2005).

    Article  PubMed  Google Scholar 

  109. Wei, E. K., Giovannucci, E., Fuchs, C. S., Willett, W. C. & Mantzoros, C. S. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J. Natl Cancer Inst. 97, 1688–1694 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Shore, S. A. et al. Effect of leptin on allergic airway responses in mice. J. Allergy Clin. Immunol. 115, 103–109 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Barbier, M. et al. Overexpression of leptin mRNA in mesenteric adipose tissue in inflammatory bowel diseases. Gastroenterol. Clin. Biol. 27, 987–991 (2003).

    CAS  PubMed  Google Scholar 

  112. Yamamoto, K. et al. Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn's disease. Gut 54, 789–796 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Siegmund, B. et al. Development of intestinal inflammation in double IL-10- and leptin-deficient mice. J. Leukocyte Biol. 76, 782–786 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Blain, A. et al. Crohn's disease clinical course and severity in obese patients. Clin. Nutr. 21, 51–57 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Schaffler, A. et al. Adipocytokines in synovial fluid. JAMA 290, 1709–1710 (2003).

    Article  PubMed  Google Scholar 

  116. Symmons, D. P. Epidemiology of rheumatoid arthritis: determinants of onset, persistence and outcome. Best Pract. Res. Clin. Rheumatol. 16, 707–722 (2002).

    Article  PubMed  Google Scholar 

  117. Yokota, T. et al. Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase–prostaglandin pathway in stromal cells. J. Immunol. 171, 5091–5099 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Pagano, C. et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J. Clin. Endocrinol. Metab. 91, 1081–1086 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Ognjanovic, S. & Bryant-Greenwood, G. D. Pre-B-cell colony-enhancing factor, a novel cytokine of human fetal membranes. Am. J. Obstet. Gynecol. 187, 1051–1058 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge A. Kaser for helpful discussions and critical reading of the manuscript. We are supported by grants from the Austrian Science Foundation and the Christian-Doppler Research Society (Austria).

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  1. Christian Doppler Research Laboratory for Gut Inflammation and Department of Medicine, Innsbruck Medical University, Anichstrasse 35, Innsbruck, 6020, Austria

    Herbert Tilg & Alexander R. Moschen

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  1. Herbert Tilg
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Correspondence to Herbert Tilg.

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Glossary

Atherosclerosis

A chronic disorder of the arterial wall characterized by endothelial damage that gradually induces deposits of cholesterol, cellular debris, calcium and other substances. These deposits finally lead to plaque formation and arterial stiffness.

Complement factors

Complement factors are components of the complement system. Activation of these factors, which involves proteolytic cleavage of serum and cell-surface glycoproteins, leads to the formation of a terminal cell-lytic complex inside the cell membrane of a target cell. Complement fragments such as C3a and C5a have important pro-inflammatory properties, such as vasodilation, chemotaxis and opsonization.

Type 2 diabetes mellitus

A disorder of glucose homeostasis that is characterized by inappropriately increased blood-glucose levels and resistance of tissues to the action of insulin. Recent studies indicate that inflammation in adipose tissue, liver and muscle contributes to the insulin-resistant state that is characteristic of type 2 diabetes mellitus, and that the anti-diabetic actions of peroxisome-proliferator-activated receptor-γ (PPARγ) agonists result, in part, from their anti-inflammatory effects in these tissues.

ob/ob mice

Mice with a spontaneous mutation in the gene encoding leptin (chromosome 6) that leads to decreased leptin production. These mice are severely obese and develop noninsulin-dependent diabetes mellitus.

Endoplasmic-reticulum stress

(ER stress). A response by the ER that results in the disruption of protein folding and in the accumulation of unfolded proteins in the ER.

Collagen-like region

The amino-terminal domain of adiponectin contains a signal sequence that is followed by a stretch of 22 collagen-like repeats, consisting of 7 perfect Gly-X-Pro repeats and 15 'imperfect' Gly-X-Y repeats (where X and Y are different amino acids), which — similar to procollagen — allows the assembly of three full-length adiponectin molecules to an adiponectin trimer.

C1q-like globular domain

The carboxy-terminal globular domain of adiponectin, which has marked homology to several other proteins, including subunits of the complement factor C1q.

Visceral obesity

Accumulation of adipose tissue inside the abdominal cavity, in particular at omental and mesenteric regions, which are drained by the portal vein and therefore have direct access to the liver.

T-cadherin

A member of the cadherin family of transmembrane glycoproteins that mediate cell-adhesive interactions.

Peroxisome-proliferator-activated receptor-γ

(PPARγ). A nuclear receptor that is a master transcriptional regulator of metabolism and fat-cell formation. The activity of PPARγ can be modulated by the direct binding of small molecules — thiazolidinediones. PPARγ has anti-inflammatory properties by limiting the availability of limited cofactors or blocking promoters of pro-inflammatory genes.

IL-1 receptor antagonist

(IL-1RA). A secreted protein that binds to IL-1R, thereby blocking IL-1R downstream signalling. IL-1RA inhibits the pro-inflammatory properties of IL-1α/β.

Carbon-tetrachloride liver-fibrosis model

Intraperitoneal or oral administration of hepatotoxic carbon tetrachloride (CCl4) to mice is a commonly used model of both acute and chronic liver injury. CCl4 causes hepatocyte injury that is characterized by centrilobular necrosis followed by hepatic fibrosis.

KK-Ay obese mice

The spontaneous Ay mutation (agouti signal protein; yellow) was introduced onto the KK strain background. KK-Ay heterozygous mice have yellow hair pigment and black eyes and develop hyperglycaemia, hyperinsulinaemia, glucose intolerance and obesity by 8 weeks of age.

Lipodystrophic transgenic mice

Transgenic mice that express a truncated, constitutively active form of the sterol-regulatory-element-binding protein 1C (SREBP1C) transcription factor under the control of the adipose-specific aP2 promoter. Lipodystrophic mice have low plasma leptin levels, hyperphagia, hyperglycaemia and hyperinsulinaemia.

Body-mass index

(BMI). This is the most frequently used method to gauge an individual's deviation from 'normal' body weight. The BMI is the quotient of body weight (in kg) through the square of height (m2). Underweight: <20; ideal: 20–25; overweight: >25; obese: >30.

Mixed lymphocyte reaction

A tissue-culture technique that is used for the in vitro testing of the proliferative response of T cells from one individual to lymphocytes from another individual.

TNF-mediated toxicity

The injection of tumour-necrosis factor (TNF) into animals, which results in acute anorexia, weight loss, shock and even death.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

Atherosclerotic aneurysm

A localized dilation of a blood vessel by more than 50% of its diameter owing to atherosclerotic structural damage of the vessel wall.

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Tilg, H., Moschen, A. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6, 772–783 (2006). https://doi.org/10.1038/nri1937

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