Regulation of Type 1 Inflammation in Diet-induced Obesity

饮食引起的肥胖中 1 型炎症的调节

基本信息

  • 批准号:
    10319966
  • 负责人:
  • 金额:
    $ 40万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-01-27 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Obesity is associated with inflammation, particularly in adipose tissue (AT), which has been implicated in obesity-linked diseases including insulin resistance and type 2 diabetes. AT inflammation is evidenced mainly by increases in “type 1 inflammation (T1I),” with elevated CD4+ T helper 1 cells (Th1), CD8+ cytotoxic T effector memory/effector cells (“Tc1”), and M1-like macrophages, but decreases in eosinophils, Th2, and M2-like macrophages. However, the transcriptional mechanisms for T1I, Th1/Tc1 in particular, in obesity have not been fully defined. In our pilot study, STAT1, a key transcription factor for immune cell polarization to T1I, was elevated and phosphorylated, indicating activation, in AT and AT T cells early and persistently in mice on high-fat diet (HFD, high in saturated fat). Strikingly, ablation of STAT1 in T cells (which include CD4+ and CD8+ T cells) in mice (tSTAT1-ko) reduced AT Th1/Tc1, raised eosinophils, and protected against HFD-induced obesity, with enhanced white AT browning, increased energy expenditure, and improved insulin resistance. In vitro study showed that Th1 repress adipocyte browning. Thus, we formed our central hypotheses that in obesity induced by HFD, AT T cells polarize into Th1/Tc1, which repress white AT browning, adversely regulate AT metabolic functions, and accelerate adiposity and insulin resistance; mechanistically, STAT1 is upregulated and activated early and persistently in AT T cells and mediates Th1/Tc1. Ablation or inhibition of STAT1 in T cells suppresses AT Th1/Tc1 polarization, with increased eosinophils but reduced M1-like macrophages, leading to “derepression” of AT browning and enhanced energy expenditure, thereby reducing adiposity and improving insulin resistance. Three aims are proposed: aim 1 will examine how STAT1 is regulated in AT T cells in HFD-induced obesity; aim 2 will examine how T cell STAT1 contributes to AT inflammation and metabolic functions in obesity including the roles of STAT1 in CD4+ vs CD8+ T cells and T cell regulation of adipocyte browning and metabolism; aim 3 will determine whether inhibition of the STAT1 pathway or inducible ablation of STAT1 in T cells reverses AT inflammation and metabolic dysfunctions in established obesity. Tissue culture with T cells from mice and humans and mouse models including mice with cell-specific constitutive or inducible ablation of STAT1, mice treated with pharmacological inhibitors of Jak/STAT1 signaling, and mice with adoptive transfer of immune cells or eosinophil depletion will be used. Flow cytometry, immunostaining, Luminex technology, NanoString system, quantitative PCR, RNA-seq, whole-body and tissue-specific metabolic function assays, and other necessary techniques will be employed. Our approach will identify a novel mechanism that regulates AT T cell T1I in obesity and examine the role of the regulatory pathway in obesity-linked inflammation and metabolic functions and the potential of targeting this pathway to prevent and treat obesity and related inflammation and metabolic disease.
肥胖与炎症有关,特别是在脂肪组织(AT)中,这与肥胖相关的疾病,包括胰岛素抵抗和2型糖尿病有关。AT炎症主要通过“1型炎症(T1 I)”的增加来证明,其中CD 4 + T辅助1细胞(Th 1)、CD 8+细胞毒性T效应记忆/效应细胞(“Tc 1”)和M1样巨噬细胞升高,但嗜酸性粒细胞、Th 2和M2样巨噬细胞减少。然而,T1 I,特别是Th 1/Tc 1在肥胖中的转录机制尚未完全确定。在我们的初步研究中,STAT 1是免疫细胞极化至T1 I的关键转录因子,在高脂饮食(HFD,高饱和脂肪)小鼠中,AT和AT T细胞早期和持续活化并磷酸化,表明活化。引人注目的是,在小鼠(tSTAT 1-ko)中,在巨噬细胞T细胞(包括CD 4+和CD 8 + T细胞)中的STAT 1的消融减少了AT Th 1/Tc 1,提高了嗜酸性粒细胞,并保护免受HFD诱导的肥胖,增加了白色AT布朗宁,增加了能量消耗,并改善了胰岛素抵抗。体外研究表明,Th 1抑制脂肪细胞布朗宁。因此,我们形成了我们的中心假设,即在HFD诱导的肥胖中,AT T细胞进入Th 1/Tc 1,其抑制白色AT布朗宁,不利地调节AT代谢功能,并加速肥胖和胰岛素抵抗;从机制上讲,STAT 1在AT T细胞中上调并早期持续激活,并介导Th 1/Tc 1。T细胞中STAT 1的消融或抑制抑制AT Th 1/Tc 1极化,嗜酸性粒细胞增加但M1样巨噬细胞减少,导致AT布朗宁的“去抑制”和能量消耗增加,从而减少肥胖和改善胰岛素抵抗。提出了三个目标:目的1将研究STAT 1在HFD诱导的肥胖中如何在AT T细胞中调节;目的2将研究T细胞STAT 1如何在肥胖中促进AT炎症和代谢功能,包括STAT 1在CD 4 + vs CD 8 + T细胞中的作用以及T细胞对脂肪细胞布朗宁和代谢的调节;目的3将确定是否抑制T细胞中的STAT 1通路或诱导性STAT 1消融逆转已确定的肥胖症中的AT炎症和代谢功能障碍。将使用来自小鼠和人的T细胞和小鼠模型的组织培养物,所述小鼠模型包括具有细胞特异性组成型或诱导型STAT 1消融的小鼠、用Jak/STAT 1信号传导的药理学抑制剂治疗的小鼠和具有免疫细胞过继转移或嗜酸性粒细胞耗竭的小鼠。将采用流式细胞术、免疫染色、Luminex技术、NanoString系统、定量PCR、RNA-seq、全身和组织特异性代谢功能测定以及其他必要技术。我们的方法将确定一种调节肥胖症AT T细胞T1 I的新机制,并研究调节途径在肥胖相关炎症和代谢功能中的作用,以及靶向该途径预防和治疗肥胖症和相关炎症和代谢疾病的潜力。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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

{{ 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 }}

Huaizhu Wu其他文献

Huaizhu Wu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('Huaizhu Wu', 18)}}的其他基金

Inflammation and insulin resistance in aging
衰老过程中的炎症和胰岛素抵抗
  • 批准号:
    10547823
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
Inflammation and insulin resistance in aging
衰老过程中的炎症和胰岛素抵抗
  • 批准号:
    10365649
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
Regulation of Type 1 Inflammation in Diet-induced Obesity
饮食引起的肥胖中 1 型炎症的调节
  • 批准号:
    10538645
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Regulation of Type 1 Inflammation in Diet-induced Obesity
饮食引起的肥胖中 1 型炎症的调节
  • 批准号:
    10089439
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Regulation of Type 1 Inflammation in Diet-induced Obesity
饮食引起的肥胖中 1 型炎症的调节
  • 批准号:
    9884494
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome
单核细胞激活和 CD11c 在肥胖相关代谢综合征中的作用
  • 批准号:
    7896076
  • 财政年份:
    2010
  • 资助金额:
    $ 40万
  • 项目类别:
Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome
单核细胞激活和 CD11c 在肥胖相关代谢综合征中的作用
  • 批准号:
    8052850
  • 财政年份:
    2010
  • 资助金额:
    $ 40万
  • 项目类别:
Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome
单核细胞激活和 CD11c 在肥胖相关代谢综合征中的作用
  • 批准号:
    8432843
  • 财政年份:
    2010
  • 资助金额:
    $ 40万
  • 项目类别:
Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome
单核细胞激活和 CD11c 在肥胖相关代谢综合征中的作用
  • 批准号:
    8231447
  • 财政年份:
    2010
  • 资助金额:
    $ 40万
  • 项目类别:

相似国自然基金

相似海外基金

Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
  • 批准号:
    321208980
  • 财政年份:
    2016
  • 资助金额:
    $ 40万
  • 项目类别:
    Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8827438
  • 财政年份:
    2014
  • 资助金额:
    $ 40万
  • 项目类别:
Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
  • 批准号:
    26450168
  • 财政年份:
    2014
  • 资助金额:
    $ 40万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
  • 批准号:
    257256526
  • 财政年份:
    2014
  • 资助金额:
    $ 40万
  • 项目类别:
    Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8828181
  • 财政年份:
    2013
  • 资助金额:
    $ 40万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8520690
  • 财政年份:
    2013
  • 资助金额:
    $ 40万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8629741
  • 财政年份:
    2013
  • 资助金额:
    $ 40万
  • 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
  • 批准号:
    23700778
  • 财政年份:
    2011
  • 资助金额:
    $ 40万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
  • 批准号:
    21780261
  • 财政年份:
    2009
  • 资助金额:
    $ 40万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
  • 批准号:
    7610781
  • 财政年份:
    2007
  • 资助金额:
    $ 40万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了