Adipose T cell microRNAs (miRs) regulate macrophage function during obesity

脂肪 T 细胞 microRNA (miR) 在肥胖期间调节巨噬细胞功能

• 批准号: 10221966
• 负责人: Udai P. Singh
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221966
• 关键词: Adipocytes; Adipose tissue; Affect; American; Anti-Inflammatory Agents; Behavioral; Blood Glucose; Body Composition; Body Weight; Body fat; CCL2 gene; Chronic; Coculture Techniques; Consumption; Data; Development; Diet; Down-Regulation; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epidemic; Eragrostis; Fasting; Fatty acid glycerol esters; Flow Cytometry; Genetic; Health; High Fat Diet; Human; Immune; Immune response; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Learning; Leptin; Mediating; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic dysfunction; MicroRNAs; Modeling; Mus; Obesity; Oligonucleotides; Overweight; Pathogenesis; Pathway interactions; Phenotype; Plasminogen; Play; Population; Prevalence; Prevention; Production; Regulation; Regulatory T-Lymphocyte; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; T-Lymphocyte; TNF gene; Testing; Therapeutic; Time; Tumor-infiltrating immune cells; United States; Weaning; Woman; adipocyte differentiation; adiponectin; base; cytokine; db/db mouse; differential expression; effector T cell; feeding; improved; in vitro testing; in vivo; inhibitor/antagonist; innovation; macrophage; mouse model; obesity development; prevent; recruit

ABSTRACT Over the past 20 years, the prevalence of obesity in the United States and worldwide has reached epidemic proportions. Obesity is a very powerful health determinant that facilitates the development and progression of several metabolic diseases, insulin resistance and chronic inflammation. High fat diet (HFD) consumption positively correlates with development of obesity. T cells infiltrate adipose tissue during the early development of obesity (prior to macrophage influx) and are strongly implicated in the initiation of inflammation associated with obesity. In both humans and mice, macrophage abundance increases in obese adipose tissue and can develop either M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes. During obesity progression differential expression of microRNAs (miRs) by naive and activated T cells suggests their importance in T cell effector (Teff) functions. Further, it is well established that miRs extensively regulate adipocyte development and function. We noticed T cell homeostatic expansion and changes in macrophage abundance and phenotype in adipose tissue of HFD fed mice compared to those fed a normal diet (ND). Specifically, our preliminary data indicates that HFD downregulates adipose resident T cell miRs-10a, -125b and -1247 and mimics miRs' in-vivo reversal of the expression of metabolic markers associated with obesity and modulates macrophage abundance. Based on strong rigor and preliminary data, our central hypothesis is that T cell miRs-10a, -125b and 1247 are essential for regulating crosstalk between adipocytes, T cells and macrophages during diet-induced obesity. To support this premise, we will test whether adipose T cell miRs play a crucial role in diet-induced obesity (DIO) (Aim 1); identify the mechanisms by which T cell miRs are downregulated in DIO (Aim 2); determine whether adipose T cell miRs mediate macrophage function in DIO (Aim 3). For the first time, we will explore how resident adipose tissue-derived T cell miRs alter metabolic function and obesity. Testing this hypothesis will provide an enhanced understanding on interactions between T cell miRs, T cell expansion, and macrophage and adipocyte function in the adipose tissue microenvironment that may allow for effective prevention and treatment options for obesity and metabolic dysfunction.

抽象的 过去20年，美国乃至全球肥胖流行率已达到流行病水平 比例。肥胖是一个非常强大的健康决定因素，可促进以下疾病的发展和进展： 多种代谢疾病、胰岛素抵抗和慢性炎症。高脂肪饮食（HFD）消耗 与肥胖的发生呈正相关。 T 细胞在早期发育过程中浸润脂肪组织 肥胖（在巨噬细胞流入之前），并且与相关炎症的引发密切相关 与肥胖。在人类和小鼠中，肥胖脂肪组织中的巨噬细胞丰度增加，并且可以 形成 M1（促炎）或 M2（抗炎）表型。肥胖进展期间 初始 T 细胞和活化 T 细胞的 microRNA (miR) 差异表达表明它们在 T 细胞中的重要性 效应器（Teff）功能。此外，众所周知，miR 广泛调节脂肪细胞的发育和 功能。我们注意到 T 细胞稳态扩张以及巨噬细胞丰度和表型的变化 HFD 喂养小鼠的脂肪组织与正常饮食 (ND) 喂养的小鼠的脂肪组织进行比较。具体来说，我们的初步数据 表明 HFD 下调脂肪驻留 T 细胞 miR-10a、-125b 和 -1247，并模拟体内 miR 逆转与肥胖相关的代谢标志物的表达并调节巨噬细胞丰度。 基于严格的初步数据，我们的中心假设是 T 细胞 miR-10a、-125b 和 1247 对于调节饮食诱导期间脂肪细胞、T 细胞和巨噬细胞之间的串扰至关重要 肥胖。为了支持这一前提，我们将测试脂肪 T 细胞 miR 是否在饮食诱导的 肥胖（DIO）（目标 1）；确定 DIO 中 T 细胞 miR 下调的机制（目标 2）；决定 脂肪 T 细胞 miR 是否介导 DIO 中的巨噬细胞功能（目标 3）。我们将首次探索 驻留脂肪组织来源的 T 细胞 miR 如何改变代谢功能和肥胖。检验这个假设将 加深对 T 细胞 miR、T 细胞扩增和巨噬细胞之间相互作用的理解 和脂肪组织微环境中的脂肪细胞功能，可以有效预防和治疗 肥胖和代谢功能障碍的治疗选择。