Letter | Published:

Depletion of fat-resident Treg cells prevents age-associated insulin resistance

Nature volume 528, pages 137141 (03 December 2015) | Download Citation

Abstract

Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR1,2,3,4,5,6, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR7 are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.

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RNA-Seq data can be accessed in the NCBI Sequence Read Archive under the accession SRP053799.

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Acknowledgements

We would like to thank L. Chong, J. Alvarez, Y. Dai, S. Kaufman and B. Collins for technical assistance, L. Ong and C. Brondos for administrative assistance, and J. Simon for assistance with graphics. S.P.B. is supported by National Institutes of Health (NIH) grants F30 DK096828 and T32 GM007198. C.L. and M.D. are funded by grants from the National Health and Medical Research Council of Australia Project grants 512354, 632886 and 1043199. R.M.E. is an Investigator of the Howard Hughes Medical Institute (HHMI) at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology, and is supported by NIH grants DK057978, DK090962, HL088093, HL105278 and ES010337, the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, California Institute for Regenerative Medicine and The Ellison Medical Foundation. Y. Zheng is supported by the Nomis Foundation, the Rita Allen Foundation, the Emerald Foundation, the Hearst Foundation, the National Multiple Sclerosis Society, and National Institutes of Health (AI099295 and AI107027). This work was also supported by National Cancer Institute funded Salk Institute Cancer Center core facilities (CA014195) and the James B. Pendleton Charitable Trust.

Author information

Affiliations

  1. Immunobiology and Microbial Pathogenesis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Sagar P. Bapat
    • , Yang Zhang
    • , Albert Cheng
    • , Carmen Zhou
    • , Yuqiong Liang
    •  & Ye Zheng
  2. Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Sagar P. Bapat
    • , Jae Myoung Suh
    • , Sungsoon Fang
    • , Sihao Liu
    • , Mathias LeBlanc
    • , Annette R. Atkins
    • , Ruth T. Yu
    • , Michael Downes
    •  & Ronald M. Evans
  3. Graduate School of Medical Science and Engineering, KAIST 34141, South Korea

    • Jae Myoung Suh
  4. Department of Biotechnology, College of Life Sciences, Sejong University, Seoul 143-747, South Korea

    • Sungsoon Fang
  5. Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Sydney 2145, Australia

    • Christopher Liddle
  6. Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Ronald M. Evans

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Contributions

S.P.B., J.M.S., M.D., R.M.E. and Y. Zheng designed and supervised the research. S.P.B., J.M.S., S.F., S.L., Y. Zhang, A.C., C.Z. and Y.L. performed research. S.P.B., J.M.S., M.L., C.L., A.R.A., R.T.Y., M.D., R.M.E. and Y. Zheng analysed data. S.P.B., J.M.S., S.L., A.R.A., R.T.Y., M.D., R.M.E. and Y. Zheng wrote the manuscript.

Competing interests

S.B., R.M.E., Y. Zheng and M.D. are co-inventors of technologies related to methods of targeting fat Treg cells to prevent insulin resistance.

Corresponding authors

Correspondence to Ronald M. Evans or Ye Zheng.

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DOI

https://doi.org/10.1038/nature16151

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