Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters


Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. These findings raise the question of how fat inflammation can escape the powerful armamentarium of cells and molecules normally responsible for guarding against a runaway immune response. CD4+ Foxp3+ T regulatory (Treg) cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but their numbers were strikingly and specifically reduced at this site in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these Treg cells influenced the inflammatory state of adipose tissue and, thus, insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These observations suggest that harnessing the anti-inflammatory properties of Treg cells to inhibit elements of the metabolic syndrome may have therapeutic potential.

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Figure 1: Abdominal (epididymal) and subcutaneous fat pads as well as spleen, lymph node, lung and liver were isolated from retired-breeder B6 male mice, and the stromovascular fraction was stained for Foxp3, CD3, CD4, CD8 and CD25.
Figure 2: Functional comparison of Treg and Tconv cells from abdominal adipose tissue, lymph node and spleen.
Figure 3: Phenotypic characterization of Treg cells from abdominal fat tissue, spleen, lung and liver.
Figure 4: Analysis of fat Treg cells in three mouse models of obesity: Lepob/ob, Ay/a and HFD.
Figure 5: Changes in inflammatory mediators and metabolic parameters in loss- and gain-of-function experiments.
Figure 6: Cytokine effects on adipocytes and human correlates.

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  1. 1

    Shoelson, S.E., Lee, J. & Goldfine, A.B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    CAS  Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Bosello, O. & Zamboni, M. Visceral obesity and metabolic syndrome. Obes. Rev. 1, 47–56 (2000).

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Lumeng, C.N., Deyoung, S.M., Bodzin, J.L. & Saltiel, A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56, 16–23 (2007).

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Suganami, T., Nishida, J. & Ogawa, Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor α. Arterioscler. Thromb. Vasc. Biol. 25, 2062–2068 (2005).

    CAS  Article  Google Scholar 

  12. 12

    Caspar-Bauguil, S. et al. Adipose tissues as an ancestral immune organ: site-specific change in obesity. FEBS Lett. 579, 3487–3492 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Zheng, Y. & Rudensky, A.Y. Foxp3 in control of the regulatory T cell lineage. Nat. Immunol. 8, 457–462 (2007).

    CAS  Article  Google Scholar 

  14. 14

    Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Maloy, K.J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Murphy, T.J., Choileain, N.N., Zang, Y., Mannick, J.A. & Lederer, J.A. CD4+CD25+ regulatory T cells control innate immune reactivity after injury. J. Immunol. 174, 2957–2963 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Nguyen, L.T., Jacobs, J., Mathis, D. & Benoist, C. Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum. 56, 509–520 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Wu, H. et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115, 1029–1038 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Tran, T.T., Yamamoto, Y., Gesta, S. & Kahn, C.R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).

    CAS  Article  Google Scholar 

  20. 20

    Cinti, S. et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).

    CAS  Article  Google Scholar 

  21. 21

    Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Huehn, J. et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J. Exp. Med. 199, 303–313 (2004).

    CAS  Article  Google Scholar 

  23. 23

    Herman, A.E., Freeman, G.J., Mathis, D. & Benoist, C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479–1489 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Hill, J. et al. Foxp3-transcription-factor–dependent and –independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Nolan, K.F. et al. IL-10–conditioned dendritic cells, decommissioned for recruitment of adaptive immunity, elicit innate inflammatory gene products in response to danger signals. J. Immunol. 172, 2201–2209 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Wong, J. et al. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J. Immunol. 178, 7032–7041 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Hsieh, C.S., Zheng, Y., Liang, Y., Fontenot, J.D. & Rudensky, A.Y. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7, 401–410 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Pacholczyk, R., Ignatowicz, H., Kraj, P. & Ignatowicz, L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 25, 249–259 (2006).

    CAS  Article  Google Scholar 

  29. 29

    Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Correia-Neves, M., Waltzinger, C., Mathis, D. & Benoist, C. The shaping of the T cell repertoire. Immunity 14, 21–32 (2001).

    CAS  Article  Google Scholar 

  31. 31

    Samad, F., Yamamoto, K., Pandey, M. & Loskutoff, D.J. Elevated expression of transforming growth factor-β in adipose tissue from obese mice. Mol. Med. 3, 37–48 (1997).

    CAS  Article  Google Scholar 

  32. 32

    Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    CAS  Article  Google Scholar 

  33. 33

    Peng, Y., Laouar, Y., Li, M.O., Green, E.A. & Flavell, R.A. TGF-β regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc. Natl. Acad. Sci. USA 101, 4572–4577 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Marie, J.C., Letterio, J.J., Gavin, M. & Rudensky, A.Y. TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067 (2005).

    CAS  Article  Google Scholar 

  35. 35

    Pelleymounter, M.A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

    CAS  Article  Google Scholar 

  36. 36

    Klebig, M.L., Wilkinson, J.E., Geisler, J.G. & Woychik, R.P. Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes and yellow fur. Proc. Natl. Acad. Sci. USA 92, 4728–4732 (1995).

    CAS  Article  Google Scholar 

  37. 37

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

    CAS  Article  Google Scholar 

  38. 38

    Kim, J.M., Rasmussen, J.P. & Rudensky, A.Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Bennett, C.L. & Clausen, B.E. DC ablation in mice: promises, pitfalls and challenges. Trends Immunol. 28, 525–531 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Thorburn, J., Frankel, A.E. & Thorburn, A. Apoptosis by leukemia cell–targeted diphtheria toxin occurs via receptor-independent activation of Fas-associated death domain protein. Clin. Cancer Res. 9, 861–865 (2003).

    CAS  PubMed  Google Scholar 

  41. 41

    Miyake, Y. et al. Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II cells. J. Immunol. 178, 5001–5009 (2007).

    CAS  Article  Google Scholar 

  42. 42

    Bennett, C.L. et al. Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity. J. Cell Biol. 169, 569–576 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Duffield, J.S. et al. Conditional ablation of macrophages halts progression of crescentic glomerulonephritis. Am. J. Pathol. 167, 1207–1219 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Duffield, J.S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

    CAS  Article  Google Scholar 

  45. 45

    Walzer, T. et al. Identification, activation and selective in vivo ablation of mouse NK cells via NKp46. Proc. Natl. Acad. Sci. USA 104, 3384–3389 (2007).

    CAS  Article  Google Scholar 

  46. 46

    Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 1673–1677 (2001).

    CAS  Article  Google Scholar 

  47. 47

    Boyman, O., Kovar, M., Rubinstein, M.P., Surh, C.D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927 (2006).

    CAS  Article  Google Scholar 

  48. 48

    Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

    CAS  Article  Google Scholar 

  49. 49

    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).

    CAS  Article  Google Scholar 

  50. 50

    Kumada, M. et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 109, 2046–2049 (2004).

    CAS  Article  Google Scholar 

  51. 51

    Kim, H.J. et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53, 1060–1067 (2004).

    CAS  Article  Google Scholar 

  52. 52

    Blüher, M. et al. Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism. Exp. Clin. Endocrinol. Diabetes 113, 534–537 (2005).

    Article  Google Scholar 

  53. 53

    Scarpelli, D. et al. Variants of the interleukin-10 promoter gene are associated with obesity and insulin resistance but not type 2 diabetes in Caucasian Italian subjects. Diabetes 55, 1529–1533 (2006).

    CAS  Article  Google Scholar 

  54. 54

    Doganci, A. et al. The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J. Clin. Invest. 115, 313–325 (2005).

    CAS  Article  Google Scholar 

  55. 55

    Wan, S., Xia, C. & Morel, L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J. Immunol. 178, 271–279 (2007).

    CAS  Article  Google Scholar 

  56. 56

    Hosogai, N. et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56, 901–911 (2007).

    CAS  Article  Google Scholar 

  57. 57

    Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114, 1752–1761 (2004).

    CAS  Article  Google Scholar 

  58. 58

    Reich, M. et al. GenePattern 2.0. Nat. Genet. 38, 500–501 (2006).

    CAS  Article  Google Scholar 

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We thank D. Littman (New York University) for the DTR construct, L. Roser and K. Hattori for assistance with mice, S. Rudensky (Memorial Sloan Kettering Cancer Center) for providing us with Foxp3DTR mice, J. LaVecchio and G. Buruzala for flow cytometry and J. Hill, J. Perez and R. Melamed for help with the microarray analysis. This work was supported by Young Chair funds to D.M. and C.B., by the US National Institutes of Health (DK51729 and DK73547) and Adler Chair funds to S.S. and by Joslin's National Institutes of Diabetes and Digestive and Kidney Diseases–funded Diabetes and Endocrinology Research Center core facilities. Postdoctoral fellowship support for M.F. was from the German Research Foundation (Emmy-Noether Fellowship, FE 801/1-1) and the Charles A. King Trust Postdoctoral Fellowship, and for L.H. from the Ministry of Science of Spain. J.W. and D.C. were supported by predoctoral fellowships from the US National Institutes of Health (T32 DK7260) and the European School of Molecular Medicine, respectively.

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Correspondence to Diane Mathis.

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Supplementary Text and Figures

Supplementary Figs. 1–8, Supplementary Tables 1–4 and Supplementary Methods (PDF 6767 kb)

Supplementary Table 5

Characteristics of adipose tissue donors (XLS 95 kb)

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Feuerer, M., Herrero, L., Cipolletta, D. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15, 930–939 (2009). https://doi.org/10.1038/nm.2002

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