Inflammation and insulin resistance in aging

衰老过程中的炎症和胰岛素抵抗

• 批准号: 10365649
• 负责人: Huaizhu Wu
• 金额: $ 39.68万
• 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/10365649
• 关键词: Ablation; Adipocytes; Adipose tissue; Age; Aging; Biological Assay; Brown Fat; Central obesity; Clinical; Data; Diet; Energy Metabolism; Fatty acid glycerol esters; Flow Cytometry; Functional disorder; Human; Impairment; Inflammaging; Inflammation; Insulin Resistance; Interferons; Knockout Mice; Knowledge; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mus; Obesity; Oleic Acids; Pathway interactions; Pharmacology; Pilot Projects; Play; Regulation; Regulatory T-Lymphocyte; Reporting; Role; STAT1 gene; Signal Transduction; Specimen; T cell therapy; T-Cell Proliferation; T-Lymphocyte; Techniques; Testing; Thinness; Tissues; Visceral; Weight Gain; Wild Type Mouse; base; dietary; immune activation; improved; inhibitor; insulin sensitivity; middle age; mouse model; novel; novel therapeutics; 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”和减少在衰老中发生的能量消耗可能有助于 与年龄相关的肥胖性，但是如何调节褐变和代谢，年龄保持不完全 理解。在炎症中，包括T细胞相关的炎症在内，代谢功能障碍已暗示 肥胖。常规T细胞（TCN）升高并促进肥胖症的炎症，而调节性 T细胞（Treg）富含倾斜度，并在肥胖中显着降低。在（Fat）Treg（Ftreg）预防 肥胖症中的炎症和胰岛素抵抗。随着衰老的衰老，TCN也升高为AT；但是与肥胖不同， 衰老的FTREG升高，可能会促进肥胖和胰岛素抵抗。差异的机制 在FTREG中，衰老和肥胖症以及TCN在年龄相关的代谢功能中的作用在很大程度上是未知的。在我们的 试点研究，渴望增加的老化小鼠的ftreg功能失调，并且反映TCN时会受到损害 增殖和TCN（伴随年龄为11个）抑制脂肪细胞褐变（均通过直接接触 脂肪细胞和分泌分子）。这是我们假设使用TCN注射的FTREG功能障碍 通过对AT AT的不利调节和 代谢。从机械上讲，STAT1是Treg调节和TCN注射的关键转录因子，是 在衰老小鼠的T细胞（包括Treg和TCN）中升高并激活 随着年龄的增长；而且，重要的是，小鼠T细胞中的STAT1消融改善了年龄相关的FTREG功能，降低了 TCN注入并防止肥胖，在褐变和能量消耗时增加，并改善 胰岛素敏感性，支持STAT1在年龄相关的FTREG功能障碍，TCN注射和 肥胖。在此应用中，我们建议进一步研究TCN和TCN和TCN细胞的作用和机制 FTREG的年龄连接炎症和代谢功能三个目标：AIM 1将研究TCN（直接驱动因素）如何 炎症）在小鼠和组织培养的年龄中有助于炎症和代谢功能； AIM 2将检查Treg（炎症调节剂）如何在炎症和代谢功能上贡献 随着老鼠的年龄； AIM 3将检查STAT1途径对饮食和药物抑制的影响 小鼠年龄相关的FTREG功能，注射和代谢功能。生成了几种新型鼠标模型 在PI的实验室和人类的标本中，带有流式细胞术，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。我们的建议旨在揭示T细胞（包括） TCN和FTREG，在衰老中有助于注射和代谢功能，可能有助于发展新颖 减轻与年龄相关的炎症并预防衰老的代谢疾病的疗法。