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OX40 promotes obesity-induced adipose inflammation and insulin resistance

Abstract

Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4+ T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation. The effects of OX40 on IR are mechanistically linked to the promotion of T cell activation, Th1 cell differentiation and proliferation—as well as the attenuation of Treg suppressive activity and the enhancement of proinflammatory cytokine production—in adipose tissues. Furthermore, OX40 expression on T cells was positively associated with obesity in humans, suggesting that our findings are clinically relevant. In summary, our study revealed that OX40 in CD4+ T cells is crucial for adipose tissue inflammation and IR development. Therefore, the OX40 signaling pathway may be a new target for preventing or treating obesity-related IR and T2DM.

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Abbreviations

APC:

Antigen presenting cell

DIO:

Diet-induced obesity

EdU:

5-Ethynyl-2′-deoxyuridine

FACS:

Fluorescence-activated cell sorting

Foxp3:

Transcription factor forkhead box P3

Gata3:

Transcription factor GATA binding protein 3

GTT:

Glucose tolerance test

HBSS:

Hanks’ balanced salt solution

HE:

Hematoxylin–eosin

HFD:

High-fat diet

IL-2:

Interleukin 2

IL-4:

Interleukin 4

IL-6:

Interleukin 6

IL-10:

Interleukin 10

IL-17a:

Interleukin 17a

IFN-γ:

Interferon-γ

IR:

Insulin resistance

ITT:

Insulin tolerance test

KO:

Knockout

mAb:

Monoclonal antibody

MHC-II:

MHC class II

NCD:

Normal control diet

NKT:

Natural killer T cells

PBMC:

Peripheral blood mononuclear cell

T2DM:

Type 2 diabetes mellitus

Tbx21:

T-box transcription factor TBX21

Th1:

T helper 1

TNF-α:

Tumor necrosis factor alpha

Tregs:

T regulatory cells

VAT:

Visceral adipose tissue

WT:

Wide type

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Acknowledgements

This work was supported by Grants from the National Natural Science Foundation of China (No. 81500598 and 81501379), Beijing Natural Science Foundation (No. 7162051, 7172060), Beijing Health System Talents Plan (2013-2-026), and the Open Project of Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation (2015YZNS04).

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Authors and Affiliations

Authors

Contributions

BL, HY and GS participated in performing the research, analyzing the data and initiating the original draft of the article. XS, HJ, CZ, DT, WS, KL, HX, XL and JY participated in performing the research and collecting the data. DZ and XH established the hypotheses, supervised the studies, analyzed the data and co-wrote the manuscript.

Corresponding authors

Correspondence to Xu Hong or Dong Zhang.

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Conflict of interest

There is no conflict of interests to be declared from all authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

18_2017_2552_MOESM1_ESM.tif

Supplementary Figure 1. The gating strategy for flow cytometry. Representative flow cytometry image of gating strategy used for flow cytometry analysis (TIFF 351 kb)

18_2017_2552_MOESM2_ESM.tif

Supplementary Figure 2. OX40 upregulation in T cells promotes DIO and IR. B6.Rag2/Il2rg double knock mice were selectively repopulated with purified CD3 T cells from WT or OX40-KO mice. After 16 weeks HFD feeding, the body weight and plasma fasting glucose levels were measured (n=5 in each group) (TIFF 108 kb)

18_2017_2552_MOESM3_ESM.tif

Supplementary Figure 3. OX40 deficiency suppressed CD4 + T cell activation and differentiation. The percentages of CD44+ cells relative to the total numbers of CD3+, CD4+ and CD8+ T cells were determined by flow cytometry in the indicated groups (n=5 in each group) (A). Absolute number of Th1 (CD4+ IFN-γ+ cells) and Treg (CD4+ Foxp3+ cells) in the adipose tissue and spleen of mice from each group (B). Flow cytometry analysis of CD4+ IL-4+ cells and CD4+ IL-17+ cells relative to the total numbers of CD4+ T cells in the adipose tissue and spleen of mice from each group, expressed as lymphocyte percentages (C) (TIFF 905 kb)

Supplementary material 4 (DOCX 29 kb)

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Liu, B., Yu, H., Sun, G. et al. OX40 promotes obesity-induced adipose inflammation and insulin resistance. Cell. Mol. Life Sci. 74, 3827–3840 (2017). https://doi.org/10.1007/s00018-017-2552-7

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  • DOI: https://doi.org/10.1007/s00018-017-2552-7

Keywords

  • Adipocyte
  • Adipose inflammation
  • Costimulation molecule
  • Diet-induced obesity
  • High-fat diet
  • IFN-γ
  • IL-17a
  • Immunology
  • Th1
  • Th17
  • Regulatory T cells