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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：
10538645
负责人：
Huaizhu Wu
金额：
$ 40万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538645
关键词：
Ablation Acceleration Adipocytes Adipose tissue Adoptive Transfer Biological Assay Blood Brown Fat CD36 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Separation Cell Surface Receptors Cells Clinical Data Diet Disease Effector Cell Energy Metabolism Flow Cytometry Genetic Transcription High Fat Diet Human Immune Immunologic Factors In Vitro Inflammation Inflammatory Insulin Resistance Knockout Mice Knowledge Link Macrophage Mediating Mediator Memory Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease PPBP gene Pathway interactions Phenotype Phosphorylation Pilot Projects Play Regulation Regulatory Pathway Regulatory T-Lymphocyte Reporting Repression Role STAT1 gene Saturated Fatty Acids Signal Transduction System T cell regulation T-Lymphocyte TLR4 gene Techniques Technology Therapeutic Thinness Tissues Unsaturated Fats Wild Type Mouse cell type cytokine cytotoxic CD8 T cells derepression diet-induced obesity eosinophil human model improved in vivo inhibitor intervention effect mouse model nano-string new therapeutic target novel obesity development pharmacologic polarized cell prevent receptor saturated fat tissue culture transcription factor transcriptome sequencing

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，尤其是脂肪组织 (AT) 中的炎症，这与肥胖相关疾病有关，包括胰岛素抵抗和 2 型糖尿病。 AT 炎症主要表现为“1 型炎症 (T1I)”增加，其中 CD4+ T 辅助 1 细胞 (Th1)、CD8+ 细胞毒性 T 效应记忆/效应细胞 (“Tc1”) 和 M1 样巨噬细胞升高，但嗜酸性粒细胞、Th2 和 M2 样巨噬细胞减少。然而，T1I（尤其是 Th1/Tc1）在肥胖中的转录机制尚未完全明确。在我们的初步研究中，STAT1（免疫细胞极化为 T1I 的关键转录因子）在高脂肪饮食（HFD，高饱和脂肪）小鼠的 AT 和 AT T 细胞中被升高并磷酸化，表明早期和持续的激活。引人注目的是，在小鼠 (tSTAT1-ko) 中去除 T 细胞（包括 CD4+ 和 CD8+ T 细胞）中的 STAT1 可减少 AT Th1/Tc1，增加嗜酸性粒细胞，并防止 HFD 诱导的肥胖，同时增强白色 AT 褐变、增加能量消耗并改善胰岛素抵抗。体外研究表明 Th1 抑制脂肪细胞褐变。因此，我们形成了我们的中心假设：在HFD引起的肥胖中，AT T细胞极化为Th1/Tc1，抑制白色AT褐变，不利地调节AT代谢功能，加速肥胖和胰岛素抵抗；从机制上讲，STAT1 在 AT T 细胞中早期且持续地上调和激活，并介导 Th1/Tc1。 T细胞中STAT1的消除或抑制可抑制AT Th1/Tc1极化，导致嗜酸性粒细胞增加，但M1样巨噬细胞减少，导致AT褐变“去抑制”并增加能量消耗，从而减少肥胖并改善胰岛素抵抗。提出了三个目标：目标 1 将研究 STAT1 在 HFD 诱导的肥胖中如何在 AT T 细胞中受到调节；目标 2 将研究 T 细胞 STAT1 如何促进肥胖中的 AT 炎症和代谢功能，包括 STAT1 在 CD4+ 与 CD8+ T 细胞中的作用以及 T 细胞对脂肪细胞褐变和代谢的调节；目标 3 将确定 T 细胞中 STAT1 通路的抑制或 STAT1 的诱导消除是否可以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类的 T 细胞的组织培养物以及小鼠模型，包括具有 STAT1 细胞特异性组成型或诱导型消融的小鼠、用 Jak/STAT1 信号传导药物抑制剂治疗的小鼠以及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的技术。我们的方法将确定一种在肥胖中调节 AT T 细胞 T1I 的新机制，并检查该调节途径在肥胖相关炎症和代谢功能中的作用，以及针对该途径预防和治疗肥胖及相关炎症和代谢疾病的潜力。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recombinant ADAMTS-13 Improves Survival of Mice Subjected to Endotoxemia.

DOI：
10.3390/ijms241411782
发表时间：
2023-07-22
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Gao, Daniel;Zhou, Zhou;Ma, Ruidong;Wu, Huaizhu;Nguyen, Trung;Liu, Li;Dong, Jingfei
通讯作者：
Dong, Jingfei

Dietary and Pharmacological Fatty Acids and Cardiovascular Health.

膳食和药理脂肪酸与心血管健康。