OX40 promotes obesity-induced adipose inflammation and insulin resistance

  • Bing Liu
  • Hengchi Yu
  • Guangyong Sun
  • Xiaojing Sun
  • Hua Jin
  • Chunpan Zhang
  • Wen Shi
  • Dan Tian
  • Kai Liu
  • Hufeng Xu
  • Xinmin Li
  • Jie Yin
  • Xu Hong
  • Dong Zhang
Original Article

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.

Keywords

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

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

Supplementary material

18_2017_2552_MOESM1_ESM.tif (352 kb)
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 (109 kb)
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 (905 kb)
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)
18_2017_2552_MOESM4_ESM.docx (29 kb)
Supplementary material 4 (DOCX 29 kb)

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Endocrinology Department, Beijing Friendship HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical UniversityBeijingPeople’s Republic of China
  3. 3.Beijing Key Laboratory of Tolerance Induction and Organ Protection in TransplantationBeijingPeople’s Republic of China
  4. 4.Beijing Clinical Research InstituteBeijingPeople’s Republic of China

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