A guanidine‐rich regulatory oligodeoxynucleotide improves type‐2 diabetes in obese mice by blocking T‐cell differentiation

Abstract

Abstract 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.

Keywords

• macrophage
• obesity
• regulatory oligodeoxynucleotide
• T‐cell differentiation
• type‐2 diabetes