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:
  • 金额:
    $ 15.58万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Lipoprotein sialylation in atherosclerosis: Lessons from mice.
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Chieko Mineo其他文献

Chieko Mineo的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Chieko Mineo', 18)}}的其他基金

A novel role of cholesterol and SR-BI in adipocyte biology
胆固醇和 SR-BI 在脂肪细胞生物学中的新作用
  • 批准号:
    10733720
  • 财政年份:
    2023
  • 资助金额:
    $ 15.58万
  • 项目类别:
Molecular Basis of Pregnancy Complications in the Antiphospholipid Syndrome
抗磷脂综合征妊娠并发症的分子基础
  • 批准号:
    9764402
  • 财政年份:
    2018
  • 资助金额:
    $ 15.58万
  • 项目类别:
Molecular Basis of Pregnancy Complications in the Antiphospholipid Syndrome
抗磷脂综合征妊娠并发症的分子基础
  • 批准号:
    10183277
  • 财政年份:
    2018
  • 资助金额:
    $ 15.58万
  • 项目类别:
Molecular Basis of Pregnancy Complications in the Antiphospholipid Syndrome
抗磷脂综合征妊娠并发症的分子基础
  • 批准号:
    10411934
  • 财政年份:
    2018
  • 资助金额:
    $ 15.58万
  • 项目类别:
Molecular Basis of Pregnancy Complications in the Antiphospholipid Syndrome
抗磷脂综合征妊娠并发症的分子基础
  • 批准号:
    9922707
  • 财政年份:
    2018
  • 资助金额:
    $ 15.58万
  • 项目类别:
Endothelial SR-BI and Metabolic Health
内皮 SR-BI 和代谢健康
  • 批准号:
    8859356
  • 财政年份:
    2015
  • 资助金额:
    $ 15.58万
  • 项目类别:
Endothelial SR-BI and Metabolic Health
内皮 SR-BI 和代谢健康
  • 批准号:
    9127359
  • 财政年份:
    2015
  • 资助金额:
    $ 15.58万
  • 项目类别:
Endothelial SR-BI and Metabolic Health
内皮 SR-BI 和代谢健康
  • 批准号:
    9302510
  • 财政年份:
    2015
  • 资助金额:
    $ 15.58万
  • 项目类别:
Discovery of Novel Interventions of the Antiphospholipid Syndrome
抗磷脂综合征的新干预措施的发现
  • 批准号:
    8501671
  • 财政年份:
    2011
  • 资助金额:
    $ 15.58万
  • 项目类别:
Discovery of Novel Interventions of the Antiphospholipid Syndrome
抗磷脂综合征的新干预措施的发现
  • 批准号:
    8326162
  • 财政年份:
    2011
  • 资助金额:
    $ 15.58万
  • 项目类别:

相似海外基金

Characterizing RNA regulation in B lymphocytes
B 淋巴细胞中 RNA 调控的特征
  • 批准号:
    502601
  • 财政年份:
    2024
  • 资助金额:
    $ 15.58万
  • 项目类别:
B Lymphocytes in Autoimmune Disease
自身免疫性疾病中的 B 淋巴细胞
  • 批准号:
    10370125
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
Characterization of Streptococcus suis interactions with B lymphocytes
猪链球菌与 B 淋巴细胞相互作用的表征
  • 批准号:
    573206-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
    University Undergraduate Student Research Awards
Myocardial-associated B lymphocytes and inflammatory injury
心肌相关B淋巴细胞与炎症损伤
  • 批准号:
    10543825
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
Altered B lymphocytes Due to Tungstate Exposure
钨酸盐暴露导致 B 淋巴细胞发生改变
  • 批准号:
    RGPIN-2020-05899
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
    Discovery Grants Program - Individual
The regulation of signaling and cytoskeletal rearrangements in B-lymphocytes
B 淋巴细胞信号传导和细胞骨架重排的调节
  • 批准号:
    RGPIN-2019-04911
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
    Discovery Grants Program - Individual
Myocardial-associated B lymphocytes and inflammatory injury
心肌相关B淋巴细胞与炎症损伤
  • 批准号:
    10339541
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
Exploring RNA helicase DDX the role of the1 at the crossroad of DNA repair processes in B lymphocytes
探索 RNA 解旋酶 DDX 在 B 淋巴细胞 DNA 修复过程十字路口的作用
  • 批准号:
    BB/X511560/1
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
    Training Grant
Role and regulation of extracellular vesicles generated in response to stimulation of CD24 on B lymphocytes
B 淋巴细胞上 CD24 刺激产生的细胞外囊泡的作用和调节
  • 批准号:
    RGPIN-2022-03800
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
    Discovery Grants Program - Individual
B Lymphocytes in Autoimmune Disease
自身免疫性疾病中的 B 淋巴细胞
  • 批准号:
    10640819
  • 财政年份:
    2022
  • 资助金额:
    $ 15.58万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了