Open AccessA guanidine‐rich regulatory oligodeoxynucleotide improves type‐2 diabetes in obese mice by blocking T‐cell differentiation
Author(s) -
Cheng Xiang,
Wang Jing,
Xia Ni,
Yan XinXin,
Tang TingTing,
Chen Han,
Zhang HongJian,
Liu Juan,
Kong Wen,
Sjöberg Sara,
Folco Eduardo,
Libby Peter,
Liao YuHua,
Shi GuoPing
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201272
Subject(s) - insulin resistance , endocrinology , medicine , adipose tissue , macrophage polarization , glucose homeostasis , type 2 diabetes , t cell , microbiology and biotechnology , chemistry , insulin , biology , macrophage , diabetes mellitus , immunology , biochemistry , in vitro , immune system
T lymphocytes exhibit pro‐inflammatory or anti‐inflammatory activities in obesity and diabetes, depending on their subtypes. Guanidine‐rich immunosuppressive oligodeoxynucleotides (ODNs) effectively control Th1/Th2‐cell counterbalance. This study reveals a non‐toxic regulatory ODN (ODNR01) that inhibits Th1‐ and Th17‐cell polarization by binding to STAT1/3/4 and blocking their phosphorylation without affecting Th2 and regulatory T cells. ODNR01 improves glucose tolerance and insulin sensitivity in both diet‐induced obese (DIO) and genetically generated obese ( ob/ob ) mice. Mechanistic studies show that ODNR01 suppresses Th1‐ and Th17‐cell differentiation in white adipose tissue, thereby reducing macrophage accumulation and M1 macrophage inflammatory molecule expression without affecting M2 macrophages. While ODNR01 shows no effect on diabetes in lymphocyte‐free Rag1‐deficient DIO mice, it enhances glucose tolerance and insulin sensitivity in CD4 + T‐cell‐reconstituted Rag1‐deficient DIO mice, suggesting its beneficial effect on insulin resistance is T‐cell‐dependent. Therefore, regulatory ODNR01 reduces obesity‐associated insulin resistance through modulation of T‐cell differentiation.