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
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9884494
• 关键词: Ablation; Adipocytes; Adipose tissue; Adoptive Transfer; Biological Assay; Blood; Brown Fat; CD36 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; 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; Insulin Resistance; Interferons; Knockout Mice; Knowledge; Link; Mediating; Mediator of activation protein; Memory; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; PPBP gene; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Pilot Projects; Play; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Reporting; Role; STAT1 gene; Saturated Fatty Acids; Signal Transduction; System; T cell regulation; T-Lymphocyte; TC1 Cell; TLR4 gene; Techniques; Technology; Therapeutic Effect; Thinness; Tissues; Unsaturated Fats; Wild Type Mouse; cell type; cytokine; cytotoxic; derepression; eosinophil; human model; improved; in vivo; inhibitor/antagonist; intervention effect; macrophage; mouse model; nano-string; new therapeutic target; novel; obesity development; polarized cell; prevent; receptor; saturated fat; tissue culture; transcription factor; transcriptome sequencing

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，该脂肪组织已在肥胖连接的疾病中浸渍，包括胰岛素抵抗和2型糖尿病。在炎症时，主要通过“ 1型炎症（T1I）”的增加来证明，CD4+ T助手1细胞（TH1），CD8+细胞毒性T效应记忆/效应细胞（“ TC1”）和M1样巨噬细胞的升高升高，但在eosinophils，Eosinophils，Th2，M2样M2，M2样MiClages。但是，尤其是肥胖症中T1I，尤其是Th1/Tc1的转录机制尚未完全定义。在我们的初步研究中，STAT1是免疫细胞极化对T1i的关键转录因子，在AT和在T细胞中升高并磷酸化，表明在TAT和在T细胞中持续且在高脂饮食中的小鼠中持续持续（HFD，高饱和脂肪）。引人注目的是，在Th1/Tc1时降低了小鼠（TSTAT1-KO）中T细胞（包括CD4+和CD8+ T细胞）中Stat1的消融，嗜酸性粒细胞升高，并保护HFD诱导的肥胖症，并在褐变时增强的白色能量，增强的能量消耗和胰岛素的耐药性，并增强了白色的肥胖症。体外研究表明，Th1复制品脂肪细胞褐变。这是我们形成的中心假设，即在HFD诱导的肥胖症中，T细胞在Th1/tc1中偏振。白色在褐变时，对代谢功能进行不利调节，并加速肥胖和胰岛素抵抗；从机械上讲，STAT1在T细胞中的早期和持久地上调和激活，并介导Th1/Tc1。 T细胞中STAT1的消融或抑制在Th1/Tc1极化下抑制，嗜酸性粒细胞增加，但减少了M1样巨噬细胞，从而导致褐变和增强的能量消耗的“消除”，从而降低肥胖性和提高胰岛素抵抗。提出了三个目的：AIM 1将检查如何在HFD诱导的肥胖症的T细胞中调节STAT1； AIM 2将检查T细胞STAT1在肥胖症中如何促进注射和代谢功能，包括STAT1在CD4+ VS CD8+ T细胞中的作用以及脂肪细胞褐变和代谢的T细胞调节； AIM 3将确定抑制STAT1途径的抑制或在既定肥胖症中注射和代谢功能障碍时在T细胞中诱导STAT1的消融。用小鼠和人类和小鼠模型（包括细胞特异性组成型或诱导的Stat1消融，用JAK/STAT1信号传导治疗的小鼠）的T细胞的组织培养。流式细胞仪，免疫染色，Luminex技术，纳米构成系统，定量PCR，RNA-SEQ，全身和组织特异性代谢功能分析以及其他必要的技术。我们的方法将确定一种新的机制，该机制在肥胖症中调节T细胞T1i并检查调节途径在肥胖连接感染和代谢功能中的作用，以及针对这种预防和治疗肥胖和相关炎症和代谢疾病的途径的潜力。