Inflammation and insulin resistance in aging

衰老过程中的炎症和胰岛素抵抗

• 批准号: 10547823
• 负责人: Huaizhu Wu
• 金额: $ 40.14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547823
• 关键词: Ablation; Adipocytes; Adipose tissue; Age; Aging; Biological Assay; Brown Fat; Cells; Central obesity; Clinical; Data; Diet; Disease; Energy Metabolism; Fatty acid glycerol esters; Flow Cytometry; Functional disorder; Human; Impairment; Inflammaging; Inflammation; Insulin Resistance; Knockout Mice; Knowledge; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mus; Obesity; Oleic Acids; Organ; Pathway interactions; Phosphorylation; Pilot Projects; Play; Regulation; Regulatory T-Lymphocyte; Reporting; Repression; Role; STAT1 gene; Signal Transduction; Specimen; T cell therapy; T-Cell Proliferation; T-Lymphocyte; T-cell inflamed; Techniques; Testing; Thinness; Tissues; Visceral; Weight Gain; Wild Type Mouse; dietary; immune activation; improved; inhibitor; insulin sensitivity; middle age; mouse model; novel; novel therapeutics; pharmacologic; prevent; tissue culture; transcription factor; transcriptome sequencing

Aging (referring to middle age) is commonly associated with visceral adiposity and insulin resistance. Impaired white adipose tissue (AT) “browning” and reduced energy expenditure that also occur in aging may contribute to age-linked adiposity, yet how AT browning and metabolism are regulated with age remains incompletely understood. AT inflammation, including T cell–related inflammation, has been implicated in metabolic dysfunction in obesity. Conventional T cells (Tcn) are elevated and promote inflammation in obese AT, whereas regulatory T cells (Treg) are enriched in lean AT and markedly reduced in obese AT. AT (fat) Treg (fTreg) protect against inflammation and insulin resistance in obesity. With aging, Tcn are also elevated in AT; but unlike in obesity, in aging fTreg are elevated and may promote adiposity and insulin resistance. The mechanism for the difference in fTreg in aging and obesity and the role of Tcn in age-linked metabolic functions are largely unknown. In our pilot study, despite increased number, fTreg in aging mice were dysfunctional and impaired in repressing Tcn proliferation, and Tcn (elevated in AT with age) inhibited adipocyte browning (both by direct contact with adipocytes and through secreted molecules). Thus, we hypothesize that fTreg dysfunction with Tcn inflammation plays a pivotal role in age-linked adiposity and insulin resistance via adverse regulation of AT browning and metabolism. Mechanistically, STAT1, a key transcription factor for Treg regulation and Tcn inflammation, was elevated and activated in AT T cells (which include Treg and Tcn) of aging mice and increased in human AT with age; and, importantly, STAT1 ablation in T cells in mice improved age-linked fTreg functions, reduced AT Tcn inflammation, and prevented adiposity, with increased AT browning and energy expenditure, and improved insulin sensitivity, supporting a pivotal role of STAT1 in age-linked fTreg dysfunction, Tcn inflammation, and adiposity. In this application, we propose to examine further the role and mechanism of T cells including Tcn and fTreg in age-linked inflammation and metabolic functions in three aims: aim 1 will examine how Tcn (direct drivers of inflammation) contribute to AT inflammation and metabolic functions with age in mice and by tissue culture; aim 2 will examine how Treg (regulators of inflammation) contribute to AT inflammation and metabolic functions with age in mice; aim 3 will examine effects of dietary and pharmacologic inhibition of the STAT1 pathway on age-linked fTreg function, inflammation, and metabolic functions in mice. Several novel mouse models generated in PI's lab and human AT specimens, with flow cytometry, quantitative PCR, RNA-seq, whole-body and tissue- specific metabolic assays, and other techniques, will be used. Our proposal aims to reveal how T cells, including Tcn and fTreg, contribute to AT inflammation and metabolic functions in aging and may help develop novel therapies to mitigate age-related inflammation and prevent metabolic disease with aging.

衰老（指中年）通常与内脏肥胖和胰岛素抵抗有关。受损 白色脂肪组织（AT）“褐变”和衰老过程中发生的能量消耗减少可能会导致 与年龄相关的肥胖，但 AT 褐变和代谢如何随年龄调节仍不完全 明白了。 AT 炎症，包括 T 细胞相关炎症，与代谢功能障碍有关 在肥胖中。肥胖 AT 中传统 T 细胞 (Tcn) 升高并促进炎症，而调节性 T 细胞 (Tcn) 升高并促进肥胖 AT 中的炎症。 T 细胞 (Treg) 在瘦 AT 中丰富，而在肥胖 AT 中显着减少。 AT（脂肪）Treg（fTreg）预防 肥胖症中的炎症和胰岛素抵抗。随着年龄的增长，AT 中的 Tcn 也会升高；但与肥胖不同的是 衰老的 fTreg 会升高，并可能促进肥胖和胰岛素抵抗。差异的机制 fTreg 在衰老和肥胖中的作用以及 Tcn 在与年龄相关的代谢功能中的作用在很大程度上尚不清楚。在我们的 初步研究显示，尽管衰老小鼠的 fTreg 数量有所增加，但其功能失调且抑制 Tcn 的能力受损 增殖和 Tcn（AT 随着年龄的增长而升高）抑制脂肪细胞褐变（均通过直接接触 脂肪细胞和通过分泌的分子）。因此，我们假设 fTreg 功能障碍与 Tcn 炎症有关 通过对 AT 褐变和胰岛素抵抗的不利调节，在与年龄相关的肥胖和胰岛素抵抗中发挥关键作用 代谢。从机制上讲，STAT1是Treg调节和Tcn炎症的关键转录因子。 在衰老小鼠的 AT T 细胞（包括 Treg 和 Tcn）中升高并被激活，在人类 AT 中也升高 随着年龄的增长；重要的是，小鼠 T 细胞中 STAT1 的消除改善了与年龄相关的 fTreg 功能，降低了 AT Tcn 炎症，并预防肥胖，增加 AT 褐变和能量消耗，并改善 胰岛素敏感性，支持 STAT1 在与年龄相关的 fTreg 功能障碍、Tcn 炎症和 肥胖。在此应用中，我们建议进一步研究 T 细胞（包括 Tcn 和 fTreg 在与年龄相关的炎症和代谢功能中的三个目标：目标 1 将研究 Tcn（直接驱动因素）如何 炎症）随着小鼠年龄的增长和组织培养，促进 AT 炎症和代谢功能； 目标 2 将研究 Treg（炎症调节因子）如何促进 AT 炎症和代谢功能 随着小鼠年龄的增长；目标 3 将检查饮食和药物抑制 STAT1 通路对 小鼠中与年龄相关的 fTreg 功能、炎症和代谢功能。生成了几种新颖的小鼠模型 在 PI 的实验室和人类 AT 样本中，使用流式细胞术、定量 PCR、RNA-seq、全身和组织- 将使用特定的代谢测定和其他技术。我们的提案旨在揭示 T 细胞（包括 Tcn 和 fTreg 有助于衰老过程中 AT 炎症和代谢功能，可能有助于开发新的 减轻与年龄相关的炎症并预防衰老引起的代谢性疾病的疗法。