Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Adipokines as emerging mediators of immune response and inflammation

Nature Clinical Practice Rheumatology volume 3, pages 716–724 (2007)Cite this article

Abstract

The scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the product of the gene obese (ob) demonstrated the role of adipose tissue in the physiopathology of obesity-related diseases, and helped to increase the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived adipokines can be considered as a hub between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, we will discuss the progress in adipokine research, focusing particular attention to the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines in inflammatory, autoimmune and rheumatic diseases.

Key Points

  • Adipokines are soluble factors produced prevalently by white adipose tissue that have emerged as modulators of inflammation and the immune response

  • Although definitive conclusions are awaited, recent evidence points to involvement of adipokines in relevant degenerative diseases such as rheumatoid arthritis and osteoarthritis

  • Although many functions of these molecules remain to be investigated, adipokines stand at the interface between metabolism and immunity in modulating not only inflammation, but also immune and autoimmune reactivity

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The multiple functions of white adipose tissue include the synthesis and secretion of adipokines, and the uptake, storage and synthesis of lipids.
Figure 2: A schematic representation of the pleiotropic nature of leptin.
Figure 3: Leptin as a regulator of bone and cartilage homestasis.

Similar content being viewed by others

References

  1. Zhang Y et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432

    Article  CAS  Google Scholar 

  2. Otero M et al. (2005) Leptin, from fat to inflammation: old questions and new insights. FEBS Lett 579: 295–301

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Hotamisligil GS et al. (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259: 87–91

    Article  CAS  Google Scholar 

  5. Tilg H et al. (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Rev Immunol 6: 772–783

    Article  CAS  Google Scholar 

  6. Dayer JM et al. (2006) Adipose tissue has anti-inflammatory properties. Ann NY Acad Sci 1069: 444–453

    Article  CAS  Google Scholar 

  7. Otero M et al. (2006) Towards a pro-inflammatory and immunomodulatory emerging role of leptin. Rheumatology (Oxford) 45: 944–950

    Article  CAS  Google Scholar 

  8. Fruhbeck G (2006) Intracellular signalling pathways activated by leptin. Biochem J 393: 7–20

    Article  CAS  Google Scholar 

  9. Gualillo O et al. (2002) Leptin promotes the tyrosine phosphorylation of SHC proteins and SHC association with GRB2. Mol Cell Endocrinol 190: 83–89

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Matarese G et al. (2005) Leptin in immunology. J Immunol 174: 3137–3142

    Article  CAS  Google Scholar 

  12. Faggioni R et al. (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 15: 2565–2571

    Article  CAS  Google Scholar 

  13. De Rosa et al. (2007) A key role of leptin in the control of regulatory T cell proliferation. Immunity 26: 241–255

    Article  Google Scholar 

  14. Otero M et al. (2006) Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis 65: 1198–1201

    Article  CAS  Google Scholar 

  15. Toussirot E et al. (2007) The contribution of adipose tissue and adipokines to inflammation in joint diseases. Curr Med Chem 14: 1095–1100

    Article  CAS  Google Scholar 

  16. Fraser DA et al. (1999) Decreased CD4+ lymphocyte activation and increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation. Clin Rheumatol 18: 394–401

    Article  CAS  Google Scholar 

  17. Bernotiene E et al. (2006) The role of leptin in innate and adaptive immune response. Arthritis Res Ther 8: 217–226

    Article  Google Scholar 

  18. Gualillo O (2007) Further evidence for leptin involvement in cartilage homeostases. Osteoarthritis Cartilage 15: 857–860

    Article  CAS  Google Scholar 

  19. Otero M et al. (2003) Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-gamma in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum 48: 404–409

    Article  CAS  Google Scholar 

  20. Otero M et al. (2005) Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther 7: R581–R591

    Article  Google Scholar 

  21. Simopoulou T et al. (2007) Differential expression of leptin and leptin's receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage 15: 872–883

    Article  CAS  Google Scholar 

  22. Iliopoulos D et al. (2007) Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention. Ann Rheum Dis [doi:10.1136/ard.2007.069377]

    Article  CAS  Google Scholar 

  23. Oh DK et al. (2007) Adiponectin in health and disease. Diabetes Obes Metab 9: 282–289

    Article  CAS  Google Scholar 

  24. Kadowaki T et al. (2005) Adiponectin and adiponectin receptors. Endocr Rev 26: 439–451

    Article  CAS  Google Scholar 

  25. Matsuzawa Y (2006) Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med 3: 35–42

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  27. Sada KE et al. (2006) Altered levels of adipocytokines in association with insulin resistance in patients with systemic lupus erythematosus. J Rheumatol 33: 1545–1552

    CAS  PubMed  Google Scholar 

  28. Ehling A et al. (2006) The potential of adiponectin in driving arthritis. J Immunol 176: 4468–4478

    Article  CAS  Google Scholar 

  29. Lago R et al. (2007) Adiponectin induces nitric oxide synthase type 2 and pro-inflammatory cytokines in chondrocytes. Ann Rheum Dis 66 (Suppl 11): 142

    Google Scholar 

  30. Steppan CM et al. (2001) The hormone resistin links obesity to diabetes. Nature 409: 307–312

    Article  CAS  Google Scholar 

  31. Harsch IA et al. (2004) Resistin levels in patients with obstructive sleep apnoea syndrome—the link to subclinical inflammation? Med Sci Monit 10: CR510–CR515

    CAS  PubMed  Google Scholar 

  32. Reilly MP et al. (2005) Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 111: 932–939

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  34. Bokarewa M et al. (2005) Resistin, an adipokine with potent proinflammatory properties. J Immunol 174: 5789–5795

    Article  CAS  Google Scholar 

  35. Senolt L et al. (2007) Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. Ann Rheum Dis 66: 458–463

    Article  CAS  Google Scholar 

  36. Fukuhara A et al. (2005) Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307: 426–430

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  38. Moschen AR et al. (2007) Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 178: 1748–1758

    Article  CAS  Google Scholar 

  39. Tatemoto K et al. (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 251: 471–476

    Article  CAS  Google Scholar 

  40. Daviaud D et al. (2006) TNFalpha up-regulates apelin expression in human and mouse adipose tissue. FASEB J 20: 1528–1530

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Park CH et al. (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276: 7806–7810

    Article  CAS  Google Scholar 

  44. Bekri S et al. (2006) Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology 131: 788–796

    Article  CAS  Google Scholar 

  45. Fleming RE (2007) Hepcidin activation during inflammation: make it STAT. Gastroenterology 132: 447–449

    Article  CAS  Google Scholar 

  46. Pietrangelo A et al. (2007) STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 132: 294–300

    Article  CAS  Google Scholar 

  47. Schaffler A et al. (2005) Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue. Biochim Biophys Acta 1732: 96–102

    Article  CAS  Google Scholar 

  48. Gerwick L et al. (2007) Gene transcript changes in individual rainbow trout livers following an inflammatory stimulus. Fish Shellfish Immunol 22: 157–171

    Article  CAS  Google Scholar 

  49. de Souza Batista CM et al. (2007) Omentin plasma levels and gene expression are decreased in obesity. Diabetes 56: 1655–1661

    Article  CAS  Google Scholar 

  50. Kuperman DA et al. (2005) Dissecting asthma using focused transgenic modeling and functional genomics. J Allergy Clin Immunol 116: 305–311

    Article  CAS  Google Scholar 

  51. Karsenty G (2006) Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab 4: 341–348

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Part of the research described in this Review was supported by the Spanish Ministry of Health through the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (contracts PI05/0525, PI030115, PI050419, PI060919 and G03/152), by the Spanish Ministry of Education & Science (BFU 2005) and/or by the Xunta de Galicia. The work of O Gualillo and F Lago is funded by the Instituto de Salud Carlos III and the Xunta de Galicia (SERGAS) through a research staff stabilization contract. The authors would like to thank R Gomez Bahamonde for his help with drawing tables and figures. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

  1. F Lago is Head of Research at the Molecular and Cellular Cardiology Research Laboratory at the Santiago University Clinical Hospital, Santiago de Compostela, Spain.,

    Francisca Lago

  2. C Dieguez is Director of the Department of Physiology at the University of Santiago de Compostela, Santiago de Compostela, Spain.,

    Carlos Dieguez

  3. J Gómez-Reino is Head of the Rheumatology Division, and O Gualillo is Head of research at the Laboratory of Neuro-endocrine Interactions in Rheumatology and Inflammatory Diseases, both at Santiago University Hospital, Santiago de Compostela, Spain.,

    Juan Gómez-Reino & Oreste Gualillo

Authors
  1. Francisca Lago
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos Dieguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juan Gómez-Reino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oreste Gualillo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oreste Gualillo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lago, F., Dieguez, C., Gómez-Reino, J. et al. Adipokines as emerging mediators of immune response and inflammation. Nat Rev Rheumatol 3, 716–724 (2007). https://doi.org/10.1038/ncprheum0674

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0674

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing