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:

Mechanisms of macrophage activation in obesity-induced insulin resistance

A Correction to this article was published on 01 May 2009

Abstract

Chronic inflammation is now recognized as a key step in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes mellitus. This low-grade inflammation is mediated by the inflammatory (classical) activation of recruited and resident macrophages that populate metabolic tissues, including adipose tissue and liver. These findings have led to the concept that infiltration by and activation of macrophages in adipose tissue are causally linked to obesity-induced insulin resistance. Studies have shown, however, that alternatively activated macrophages taking residence in adipose tissue and liver perform beneficial functions in obesity-induced metabolic disease. Alternatively activated macrophages reduce insulin resistance in obese mice by attenuating tissue inflammation and increasing oxidative metabolism in liver and skeletal muscle. The discovery that distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance suggests that pathways controlling macrophage activation can potentially be targeted to treat these comorbidities of obesity. Thus, this Review focuses on the stimuli and mechanisms that control classical and alternative activation of tissue macrophages, and how these macrophage activation programs modulate insulin action in peripheral tissues. The functional importance of macrophage activation is further discussed in the context of host defense to highlight the crosstalk between innate immunity and metabolism.

Key Points

  • Chronic, low-grade inflammation provides a molecular pathway that links obesity to insulin resistance

  • Distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance

  • Classically activated macrophages potentiate insulin resistance

  • Alternatively activated macrophages confer protection against obesity and insulin resistance

  • Obesity induces a switch in macrophage activation, leading to increased insulin resistance

  • Peroxisome proliferator-activated receptors γ and δ regulate alternative activation of macrophages

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

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

Figure 1: Classical and alternative activation of macrophages.
Figure 2: Innate immune modules deployed in host defense and obesity.
Figure 3: Transcriptional model for alternative macrophage activation.

Similar content being viewed by others

References

  1. Flegal KM et al. (2002) Prevalence and trends in obesity among US adults, 1999-2000. JAMA 288: 1723–1727

    Article  Google Scholar 

  2. Li Z et al. (2005) Health ramifications of the obesity epidemic. Surg Clin North Am 85: 681–701

    Article  Google Scholar 

  3. Ford ES (2005) Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 28: 1769–1778

    Article  Google Scholar 

  4. Allison DB et al. (1999) The direct health care costs of obesity in the United States. Am J Public Health 89: 1194–1199

    Article  CAS  Google Scholar 

  5. Olshansky SJ et al. (2005) A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 352: 1138–1145

    Article  CAS  Google Scholar 

  6. Stumvoll M et al. (2005) Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365: 1333–1346

    Article  CAS  Google Scholar 

  7. Kadowaki T (2000) Insights into insulin resistance and type 2 diabetes from knockout mouse models. J Clin Invest 106: 459–465

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Evans RM et al. (2004) PPARs and the complex journey to obesity. Nat Med 10: 355–361

    Article  CAS  Google Scholar 

  10. Lin J et al. (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell. Metabolism 1: 361–370

    Article  Google Scholar 

  11. Shoelson SE et al. (2006) Inflammation and insulin resistance. J Clin Invest 116: 1793–1801

    Article  CAS  Google Scholar 

  12. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444: 860–867

    Article  CAS  Google Scholar 

  13. Bouloumié A et al. (2005) Role of macrophage tissue infiltration in metabolic diseases. Curr Opin Clin Nutr Metab Care 8: 347–354

    Article  Google Scholar 

  14. Ferrante AW Jr (2007) Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med 262: 408–414

    Article  CAS  Google Scholar 

  15. Medzhitov R and Janeway C Jr (2000) Innate immunity. N Engl J Med 343: 338–344

    Article  CAS  Google Scholar 

  16. Takeda K et al. (2003) Toll-like receptors. Annu Rev Immunol 21: 335–376

    Article  CAS  Google Scholar 

  17. Medzhitov R and Janeway CA Jr (1998) Innate immune recognition and control of adaptive immune responses. Semin Immunol 10: 351–353

    Article  CAS  Google Scholar 

  18. Weisberg SP et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796–1808

    Article  CAS  Google Scholar 

  19. 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 

  20. Lumeng CN et al. (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175–184

    Article  CAS  Google Scholar 

  21. Odegaard JI et al. (2007) Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447: 1116–1120

    Article  CAS  Google Scholar 

  22. Racanelli V and Rehermann B (2006) The liver as an immunological organ. Hepatology 43 (Suppl 1): S54–S62

    Article  CAS  Google Scholar 

  23. Li Z et al. (2005) Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 42: 880–885

    Article  CAS  Google Scholar 

  24. Kintscher U 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. Arterioscler Thromb Vasc Biol 28: 1304–1310

    Article  CAS  Google Scholar 

  25. Fox CJ et al. (2005) Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 5: 844–852

    Article  CAS  Google Scholar 

  26. Knight SC (2008) Specialized perinodal fat fuels and fashions immunity. Immunity 28: 135–138

    Article  CAS  Google Scholar 

  27. Wolowczuk I et al. (2008) Feeding our immune system: impact on metabolism. Clin Dev Immunol 2008: 639803

    Article  Google Scholar 

  28. Gordon S and Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5: 953–964

    Article  CAS  Google Scholar 

  29. Goerdt S et al. (1999) Alternative versus classical activation of macrophages. Pathobiology 67: 222–226

    Article  CAS  Google Scholar 

  30. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3: 23–35

    Article  CAS  Google Scholar 

  31. Martinez FO et al. (2008) Macrophage activation and polarization. Front Biosci 13: 453–461

    Article  CAS  Google Scholar 

  32. Modolell M et al. (1995) Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol 25: 1101–1104

    Article  CAS  Google Scholar 

  33. Munder M et al. (1999) Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol 163: 3771–3777

    CAS  PubMed  Google Scholar 

  34. Hotamisligil GS (2003) Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 27 (Suppl 3): S53–S55

    Article  CAS  Google Scholar 

  35. Perreault M and Marette A (2001) Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7: 1138–1143

    Article  CAS  Google Scholar 

  36. Uysal KT et al. (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389: 610–614

    Article  CAS  Google Scholar 

  37. Weisberg SP et al. (2005) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116: 115–124

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Kamei N et al. (2006) Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 281: 26602–26614

    Article  CAS  Google Scholar 

  40. Shi H et al. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116: 3015–3025

    Article  CAS  Google Scholar 

  41. Kim F et al. (2007) Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100: 1589–1596

    Article  CAS  Google Scholar 

  42. Nguyen MT et al. (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282: 35279–35292

    Article  CAS  Google Scholar 

  43. Hirosumi J et al. (2002) A central role for JNK in obesity and insulin resistance. Nature 420: 333–336

    Article  CAS  Google Scholar 

  44. Arkan MC et al. (2005) IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 11: 191–198

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  46. Solinas G et al. (2007) JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 6: 386–397

    Article  CAS  Google Scholar 

  47. Vats D et al. (2006) Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation. Cell Metab 4: 13–24

    Article  CAS  Google Scholar 

  48. Odegaard JI et al. (2008) Alterative M2 activation of Kupffer cells by PPARδ ameliroates insulin resistance. Cell Metab 7: 496–507

    Article  CAS  Google Scholar 

  49. Gallardo-Soler A et al. (2008) Arginase I induction by modified lipoproteins in macrophages: a PPARγ/δ-mediated effect that links lipid metabolism and immunity. Mol Endocrinol 22: 1394–1402

    Article  CAS  Google Scholar 

  50. Hevener AL et al. (2007) Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 117: 1658–1669

    Article  CAS  Google Scholar 

  51. Kang K et al. (2008) Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity. Cell Metab 7: 485–495

    Article  CAS  Google Scholar 

  52. Newsholme P and Newsholme EA (1989) Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture. Biochem J 261: 211–218

    Article  CAS  Google Scholar 

  53. Cramer T et al. (2003) HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112: 645–657

    Article  CAS  Google Scholar 

  54. Cawthorn WP and Sethi JK (2008) TNF-α and adipocyte biology. FEBS Lett 582: 117–131

    Article  CAS  Google Scholar 

  55. Puigserver P et al. (2001) Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARγ coactivator-1. Mol Cell 8: 971–982

    Article  CAS  Google Scholar 

  56. Bruce CR and Dyck DJ (2004) Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-α. Am J Physiol Endocrinol Metab 287: E616–62157

    Article  CAS  Google Scholar 

  57. Lowell BB and Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307: 384–387

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A Loh for critical reading of the manuscript. This work was supported by grants made available to A Chawla from NIH (DK062386 and HL076746), Takeda Pharmaceuticals of North America, and the American Diabetes Association. Support was provided to JI Odegaard by Stanford Medical Scientist Training Program and the AHA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ajay Chawla.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Odegaard, J., Chawla, A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Rev Endocrinol 4, 619–626 (2008). https://doi.org/10.1038/ncpendmet0976

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0976

This article is cited by

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