These authors contributed equally to this work.
A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation
Article first published online: 2 OCT 2012
Copyright © 2012 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 4, Issue 10, pages 1112–1125, October 2012
How to Cite
Cheng, X., Wang, J., Xia, N., Yan, X.-X., Tang, T.-T., Chen, H., Zhang, H.-J., Liu, J., Kong, W., Sjöberg, S., Folco, E., Libby, P., Liao, Y.-H. and Shi, G.-P. (2012), A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation. EMBO Mol Med, 4: 1112–1125. doi: 10.1002/emmm.201201272
- Issue published online: 2 OCT 2012
- Article first published online: 2 OCT 2012
- Manuscript Accepted: 8 AUG 2012
- Manuscript Revised: 1 AUG 2012
- Manuscript Received: 9 FEB 2012
- Funded Access
- regulatory oligodeoxynucleotide;
- T-cell differentiation;
- type-2 diabetes
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.