PMID- 29202472
OWN - NLM
STAT- MEDLINE
DCOM- 20190507
LR  - 20190507
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 128
IP  - 1
DP  - 2018 Jan 2
TI  - Hyposialylated IgG activates endothelial IgG receptor FcgammaRIIB to promote 
      obesity-induced insulin resistance.
PG  - 309-322
LID - 89333 [pii]
LID - 10.1172/JCI89333 [doi]
AB  - Type 2 diabetes mellitus (T2DM) is a common complication of obesity. Here, we 
      have shown that activation of the IgG receptor FcgammaRIIB in endothelium by 
      hyposialylated IgG plays an important role in obesity-induced insulin resistance. 
      Despite becoming obese on a high-fat diet (HFD), mice lacking FcgammaRIIB globally or 
      selectively in endothelium were protected from insulin resistance as a result of 
      the preservation of insulin delivery to skeletal muscle and resulting maintenance 
      of muscle glucose disposal. IgG transfer in IgG-deficient mice implicated IgG as 
      the pathogenetic ligand for endothelial FcgammaRIIB in obesity-induced insulin 
      resistance. Moreover, IgG transferred from patients with T2DM but not from 
      metabolically healthy subjects caused insulin resistance in IgG-deficient mice 
      via FcgammaRIIB, indicating that similar processes may be operative in T2DM in 
      humans. Mechanistically, the activation of FcgammaRIIB by IgG from obese mice 
      impaired endothelial cell insulin transcytosis in culture and in vivo. These 
      effects were attributed to hyposialylation of the Fc glycan, and IgG from T2DM 
      patients was also hyposialylated. In HFD-fed mice, supplementation with the 
      sialic acid precursor N-acetyl-D-mannosamine restored IgG sialylation and 
      preserved insulin sensitivity without affecting weight gain. Thus, IgG 
      sialylation and endothelial FcgammaRIIB may represent promising therapeutic targets 
      to sever the link between obesity and T2DM.
FAU - Tanigaki, Keiji
AU  - Tanigaki K
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Sacharidou, Anastasia
AU  - Sacharidou A
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Peng, Jun
AU  - Peng J
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Chambliss, Ken L
AU  - Chambliss KL
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Yuhanna, Ivan S
AU  - Yuhanna IS
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Ghosh, Debabrata
AU  - Ghosh D
AD  - Department of Bioengineering, University of Texas at Dallas, Richardson Texas, 
      USA.
AD  - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA.
FAU - Ahmed, Mohamed
AU  - Ahmed M
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Szalai, Alexander J
AU  - Szalai AJ
AD  - Division of Clinical Immunology and Rheumatology, Department of Medicine, 
      University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Vongpatanasin, Wanpen
AU  - Vongpatanasin W
AD  - Hypertension Section, Division of Cardiology, Department of Internal Medicine, 
      University of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Mattrey, Robert F
AU  - Mattrey RF
AD  - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA.
FAU - Chen, Qiushi
AU  - Chen Q
AD  - The Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, 
      USA.
FAU - Azadi, Parastoo
AU  - Azadi P
AD  - The Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, 
      USA.
FAU - Lingvay, Ildiko
AU  - Lingvay I
AD  - Division of Endocrinology, Diabetes, and Metabolism and Department of Clinical 
      Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Botto, Marina
AU  - Botto M
AD  - Centre for Complement and Inflammation Research, Division of Immunology and 
      Inflammation, Department of Medicine, Imperial College London, London, United 
      Kingdom.
FAU - Holland, William L
AU  - Holland WL
AD  - Touchstone Diabetes Center, Department of Internal Medicine, and.
FAU - Kohler, Jennifer J
AU  - Kohler JJ
AD  - Department of Biochemistry, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Sirsi, Shashank R
AU  - Sirsi SR
AD  - Department of Bioengineering, University of Texas at Dallas, Richardson Texas, 
      USA.
AD  - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA.
FAU - Hoyt, Kenneth
AU  - Hoyt K
AD  - Department of Bioengineering, University of Texas at Dallas, Richardson Texas, 
      USA.
AD  - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA.
FAU - Shaul, Philip W
AU  - Shaul PW
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
FAU - Mineo, Chieko
AU  - Mineo C
AD  - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University 
      of Texas Southwestern Medical Center, Dallas, Texas, USA.
LA  - eng
GR  - R01 DK099092/DK/NIDDK NIH HHS/United States
GR  - R01 HL115122/HL/NHLBI NIH HHS/United States
GR  - K25 EB017222/EB/NIBIB NIH HHS/United States
GR  - R01 DK108833/DK/NIDDK NIH HHS/United States
GR  - R01 GM090271/GM/NIGMS NIH HHS/United States
GR  - R01 DK110127/DK/NIDDK NIH HHS/United States
GR  - P41 GM103490/GM/NIGMS NIH HHS/United States
GR  - T32 HL098040/HL/NHLBI NIH HHS/United States
GR  - R21 CA212851/CA/NCI NIH HHS/United States
GR  - S10 OD018530/OD/NIH HHS/United States
GR  - K23 RR024470/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171127
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Fcgr2b protein, mouse)
RN  - 0 (Hexosamines)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, IgG)
RN  - X80PR7P73R (N-acetylmannosamine)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Type 2/genetics/*metabolism/pathology
MH  - Endothelial Cells/metabolism/pathology
MH  - Hexosamines/pharmacology
MH  - Immunoglobulin G/genetics/*metabolism
MH  - *Insulin Resistance
MH  - Mice
MH  - Mice, Knockout
MH  - Obesity/genetics/*metabolism/pathology
MH  - Receptors, IgG/genetics/*metabolism
MH  - Transcytosis/drug effects
PMC - PMC5749535
OTO - NOTNLM
OT  - Metabolism
OT  - Mouse models
OT  - Obesity
OT  - Vascular Biology
OT  - endothelial cells
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2017/12/05 06:00
MHDA- 2019/05/08 06:00
PMCR- 2018/04/02
CRDT- 2017/12/05 06:00
PHST- 2016/06/30 00:00 [received]
PHST- 2017/10/17 00:00 [accepted]
PHST- 2017/12/05 06:00 [pubmed]
PHST- 2019/05/08 06:00 [medline]
PHST- 2017/12/05 06:00 [entrez]
PHST- 2018/04/02 00:00 [pmc-release]
AID - 89333 [pii]
AID - 10.1172/JCI89333 [doi]
PST - ppublish
SO  - J Clin Invest. 2018 Jan 2;128(1):309-322. doi: 10.1172/JCI89333. Epub 2017 Nov 
      27.