title: A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation.
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.
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technolog, Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China. nathancx@mail.hust.edu.cn
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Ni
authors.initials: N
authors.lastname: Xia
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Yan
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Tang
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Wen
authors.initials: W
authors.lastname: Kong
authors.forename: Sara
authors.initials: S
authors.lastname: Sjöberg
authors.forename: Eduardo
authors.initials: E
authors.lastname: Folco
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D050797:STAT4 Transcription Factor / Q000037:antagonists & inhibitors; D018417:Th1 Cells / Q000187:drug effects*; D058504:Th17 Cells / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494091:Stat4 protein, mouse