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
• 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 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

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，肥胖症中T1 I（特别是Th 1/Tc 1）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

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。

• DOI: 10.1210/clinem/dgz174
• 发表时间: 2020
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Wu,Huaizhu;Xu,Lu;Ballantyne,ChristieM
• 通讯作者: Ballantyne,ChristieM

Loss of bone morphogenetic protein-binding endothelial regulator causes insulin resistance.

• DOI: 10.1038/s41467-021-22130-2
• 发表时间: 2021-03-26
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mao H;Li L;Fan Q;Angelini A;Saha PK;Wu H;Ballantyne CM;Hartig SM;Xie L;Pi X
• 通讯作者: Pi X

Monocyte phenotyping and management of lipoprotein X syndrome.

• DOI: 10.1016/j.jacl.2020.08.012
• 发表时间: 2020-11
• 期刊: Journal of clinical lipidology
• 影响因子: 4.4
• 作者: Lian Z;Saeed A;Peng X;Perrard XD;Jia X;Hussain A;Ballantyne CM;Wu H
• 通讯作者: Wu H

Dietary Effects on Monocyte Phenotypes in Subjects With Hypertriglyceridemia and Metabolic Syndrome.

• DOI: 10.1016/j.jacbts.2023.02.011
• 发表时间: 2023-05
• 期刊: JACC-BASIC TO TRANSLATIONAL SCIENCE
• 影响因子: 9.7
• 作者: Lian, Zeqin;Perrard, Xiao-Yuan Dai;Antony, Antu Kalathookunnel;Peng, Xueying;Xu, Lu;Ni, Jing;Zhang, Bingqian;'Brien, Veronica;Saeed, Anum;Jia, Xiaoming;Hussain, Aliza;Yu, Bing;Simon, Scott I.;Sacks, Frank M.;Hoogeveen, Ron C.;Ballantyne, Christie M.;Wu, Huaizhu
• 通讯作者: Wu, Huaizhu