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Endothelial Basis of Obesity-induced Insulin Resistance

肥胖引起的胰岛素抵抗的内皮基础

基本信息

批准号：
10004231
负责人：
Chieko Mineo
金额：
$ 15.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004231
关键词：
Address B-Lymphocytes Binding Blood Circulation Cell Culture Techniques Chronic Cultured Cells Diet Down-Regulation Effector Cell Endothelial Cells Endothelium Fc Receptor Fc domain Galactosides Genetically Engineered Mouse Glucose Goals High Fat Diet Human IgG Receptors Immune system Immunoglobulin G Impairment Inflammatory Injections Insulin Insulin Resistance Knockout Mice Knowledge Ligands LoxP-flanked allele Measures Mediating Metabolism Modification Mouse Strains Mus Muscle Muscle Fibers N-acetylmannosamine Neuraminidase Non-Insulin-Dependent Diabetes Mellitus Obesity Operative Surgical Procedures Pathogenesis Patients Peripheral Plasma Preventive Preventive treatment Process Proteins Regulation Research Project Grants Role Sialic Acids Signal Pathway Signal Transduction Site Skeletal Muscle Testing Thinness Up-Regulation Wild Type Mouse attenuation bariatric surgery base cadherin 5 cohort combat experimental study feeding glucose metabolism glycosylation human subject insulin sensitivity mannosamine mouse model novel prevent receptor sialylation translational approach uptake

项目摘要

Project Summary/Abstract Fc receptors (FcR) modulate intracellular signaling upon IgG binding in the effector cells in the immune system. We have previously found that the inhibitory FcR known as FcγRIIB is also expressed in skeletal muscle microvascular endothelium, and that global FcγRIIB null mice are protected from high-fat diet (HFD)-induced insulin resistance. To explore the role of endothelial FcγRIIB in insulin metabolism, we generated the mouse strain lacking FcγRIIB specifically in endothelial cells by crossing floxed FcγRIIB (FcγRIIBfl/fl) with VE Cadherin-Cre mice (FcγRIIBfl/fl:VECad-Cre), and fed them with control diet or HFD. We found that FcγRIIBfl/fl:VECad-Cre mice are protected from HFD-induced peripheral insulin resistance and from impairment of glucose delivery to the skeletal muscle. Furthermore, we discovered that IgG isolated from HFD-fed wild-type mice (HFD-IgG), but not IgG from control diet-fed mice (Con-IgG), induces insulin resistance when transferred into mice lacking endogenous IgG (B-/- mice) in an FcγRIIB dependent manner, and that HFD-IgG is less sialylated in its Fc domain compared to Con-IgG. Treatment of wild-type mice with N-Acetyl-D-mannosamine (ManNAc) that increases protein sialylation ameliorated HFD-induced insulin resistance. Moreover, IgG isolated from obese type 2 diabetes mellitus (T2DM) patients, but not from non-T2DM subjects, induced insulin resistance in B-/- mice via FcγRIIB. Based upon these novel findings, the overall goal of the proposed project is to determine how IgG sialylation is dysregulated in diet-induced obesity (DIO) and how endothelial FcγRIIB contributes to the pathogenesis of DIO-related insulin resistance using both mouse models and cultured cells. Aim 1 will determine how HFD decreases sialylation of IgG, focusing on the process in B cells that modulates IgG sialylation. We will also determine how ManNAc prevents HFD-induced insulin resistance. Aim 2 will determine how endothelial FcγRIIB mediates HFD-induced peripheral insulin resistance, testing the hypothesis that activation of endothelial FcγRIIB by HFD-IgG initiates intracellular signaling that leads to attenuation of transendothelial transport of insulin. Aim 3 will determine whether IgG sialylation and its ability to induce insulin resistance in mice are associated with DIO-related insulin resistance in humans, using existing cohorts of subjects with a range of obesity and insulin sensitivity. Using a highly translational approach, we will test the novel concept that FcγRIIB in endothelium and modification of IgG in B cells are critically involved in the pathogenesis of insulin resistance and T2DM. We anticipate that the new knowledge gained will lead to novel preventative and treatment measures to combat the insulin resistance that characterizes obesity and other chronic inflammatory conditions.

项目总结/文摘