Cheng, XiangWang, JingXia, NiYan, Xin-XinTang, Ting-TingChen, HanZhang, Hong-JianLiu, JuanKong, WenSjöberg, SaraFolco, EduardoLibby, PeterLiao, Yu-HuaShi, Guo-Ping2013-04-262012Cheng, Xiang, Jing Wang, Ni Xia, Xin-Xin Yan, Ting-Ting Tang, Han Chen, Hong-Jian Zhang, et al. 2012. A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation. EMBO Molecular Medicine 4(10): 1112-1125.1757-4676http://nrs.harvard.edu/urn-3:HUL.InstRepos:10589815T 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.en-USmacrophageobesityregulatory oligodeoxynucleotideT-cell differentiationtype-2 diabetesJournal Article2013-04-2610.1002/emmm.201201272