Letter | Published:

Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes

Nature volume 514, pages 237241 (09 October 2014) | Download Citation


The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established1,2. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome3,4,5. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine6,7. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4+ T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.

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  1. 1.

    & Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012)

  2. 2.

    et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006)

  3. 3.

    & Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011)

  4. 4.

    & Immunological complications of obesity. Nature Immunol. 13, 707–712 (2012)

  5. 5.

    et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010)

  6. 6.

    , , , & Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011)

  7. 7.

    Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15–23 (2009)

  8. 8.

    , & Mechanisms of leptin action and leptin resistance. Annu. Rev. Physiol. 70, 537–556 (2008)

  9. 9.

    et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008)

  10. 10.

    et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008)

  11. 11.

    et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012)

  12. 12.

    et al. Leptin signaling in intestinal epithelium mediates resistance to enteric infection by Entamoeba histolytica. Mucosal Immunol. 4, 294–303 (2011)

  13. 13.

    et al. TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3negCD127+ immune cells in spleen and mucosa. J. Immunol. 185, 1177–1185 (2010)

  14. 14.

    , & Leptin as an immunomodulator. Mol. Aspects Med. 33, 35–45 (2012)

  15. 15.

    et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998)

  16. 16.

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

  17. 17.

    et al. Leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J. Immunol. 190, 3054–3058 (2013)

  18. 18.

    et al. Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies. Infect. Immun. 72, 3315–3324 (2004)

  19. 19.

    & Gut microbiome, obesity, and metabolic dysfunction. J. Clin. Invest. 121, 2126–2132 (2011)

  20. 20.

    et al. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339, 218–222 (2013)

  21. 21.

    , , & Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997)

  22. 22.

    et al. Targeted disruption of the tumor necrosis factor-α gene: metabolic consequences in obese and nonobese mice. Diabetes 46, 1526–1531 (1997)

  23. 23.

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

  24. 24.

    et al. Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice. Diabetes 60, 486–495 (2011)

  25. 25.

    et al. Gut hormone PYY3–36 physiologically inhibits food intake. Nature 418, 650–654 (2002)

  26. 26.

    et al. Inhibition of food intake in obese subjects by peptide YY3–36. N. Engl. J. Med. 349, 941–948 (2003)

  27. 27.

    et al. A novel long-acting selective neuropeptide Y2 receptor polyethylene glycol-conjugated peptide agonist reduces food intake and body weight and improves glucose metabolism in rodents. J. Pharmacol. Exp. Ther. 323, 692–700 (2007)

  28. 28.

    et al. Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J. Hepatol. 53, 339–347 (2010)

  29. 29.

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

  30. 30.

    et al. Fat signals - lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 15, 279–291 (2012)

  31. 31.

    et al. Interleukin-22, a Th17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007)

  32. 32.

    & A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959)

  33. 33.

    et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4, 611–617 (1999)

  34. 34.

    et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nature Immunol. 12, 941–948 (2011)

  35. 35.

    et al. Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci. Translat. Med. 3, 113ra126 (2011)

  36. 36.

    et al. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect. Immun. 76, 907–915 (2008)

  37. 37.

    et al. SIGIRR, a negative regulator of TLR/IL-1R signalling promotes microbiota dependent resistance to colonization by enteric bacterial pathogens. PLoS Pathog. 9, e1003539 (2013)

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We acknowledge S. Haller for her work in pathological analysis of colon samples. We thank F. Chu and J. Eastham-Anderson for performing the immunohistochemical staining and analysing pancreatic cell staining.

Author information

Author notes

    • Xiaoting Wang
    • , Naruhisa Ota
    •  & Ganesh Kolumam

    These authors contributed equally to this work.


  1. Department of Immunology, Genentech, South San Francisco, California 94080, USA

    • Xiaoting Wang
    • , Naruhisa Ota
    • , Paolo Manzanillo
    • , Celine Eidenschenk
    • , Juan Zhang
    • , Justin Lesch
    • , Wyne P. Lee
    •  & Wenjun Ouyang
  2. Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA

    • Lance Kates
    • , Jose Zavala-Solorio
    • , Jed Ross
    • , Nicholas van Bruggen
    •  & Ganesh Kolumam
  3. Department of Pathology, Genentech, South San Francisco, California 94080, USA

    • Lauri Diehl


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W.O. and G.K. devised the project. X.W. and N.O. designed and performed most of the experiments and analyses. P.M. performed western blot and contributed to lipid metabolism studies. G.K., L.K., J.Z.-S., and J.R. contributed to metabolic studies. C.E. and J.L. contributed to flagellin stimulation studies. J.Z. and W.P.L. contributed to ovalbumin/complete Freund’s adjuvant stimulation studies. L.D. did all histology analyses. W.O., X.W., and N.O. prepared the manuscript. N.v.B., P.M., C.E., and G.K. helped to edit the manuscript.

Competing interests

All authors are employees of Genentech Inc.

Corresponding authors

Correspondence to Ganesh Kolumam or Wenjun Ouyang.

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