Article | Published:

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

Nature Medicine volume 15, pages 930939 (2009) | Download Citation

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Abstract

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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Acknowledgements

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.

Author information

Author notes

    • Markus Feuerer
    • , Laura Herrero
    • , Daniela Cipolletta
    • , Jamie Wong
    • , Christophe Benoist
    •  & Diane Mathis

    Present addresses: Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA (M.F., D.C., C.B. and D.M.); Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain (L.H.); Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA (J.W.).

Affiliations

  1. Immunology and Immunogenetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Markus Feuerer
    • , Daniela Cipolletta
    • , Jamie Wong
    • , Christophe Benoist
    •  & Diane Mathis
  2. Cellular and Molecular Physiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Laura Herrero
    • , Afia Naaz
    • , Ali Nayer
    • , Jongsoon Lee
    •  & Steven Shoelson
  3. Clinical Research, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Allison B Goldfine
  4. European School of Molecular Medicine, Naples, Italy.

    • Daniela Cipolletta

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Correspondence to Diane Mathis.

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    Supplementary Figs. 1–8, Supplementary Tables 1–4 and Supplementary Methods

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    Supplementary Table 5

    Characteristics of adipose tissue donors

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DOI

https://doi.org/10.1038/nm.2002

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