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)通常与内脏肥胖症和胰岛素抵抗有关。受损的 白色脂肪组织(AT)“褐变”和能量消耗减少，这也发生在衰老过程中，这可能有助于 年龄相关性肥胖症，但AT褐变和代谢如何随年龄调节仍不完全 明白了。AT炎症，包括与T细胞相关的炎症，与代谢功能障碍有关 在肥胖方面。常规T细胞(TCN)升高并促进肥胖AT的炎症，而调节性AT T细胞(Treg)在瘦肉型AT中丰富，在肥胖型AT中显著减少。AT(胖)Treg(FTreg)预防 肥胖症的炎症和胰岛素抵抗。随着年龄的增长，AT患者的TCN也会升高；但与肥胖不同的是，在 衰老的fTreg升高，可能会促进肥胖和胰岛素抵抗。造成这种差异的机制 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是未知的。在我们的 初步研究，尽管数量增加，但衰老小鼠的fTreg功能障碍，在抑制TCN方面受损 增殖和TCN(AT中随年龄升高)抑制脂肪细胞褐化(两者都是通过直接接触 通过脂肪细胞和分泌分子)。因此，我们假设fTreg功能障碍与TCN炎症有关 在年龄相关性肥胖和胰岛素抵抗中起关键作用，其机制是通过对AT褐变和胰岛素抵抗的逆向调节 新陈代谢。STAT1是Treg调节和TCN炎症的关键转录因子，从机制上讲，它是 衰老小鼠AT-T细胞(包括Treg和Tcn)的升高和激活，以及人AT的升高 随着年龄的增长，重要的是，去除小鼠T细胞中的STAT1可以改善与年龄相关的fTreg功能，降低AT TCN发炎，预防肥胖，增加AT褐变和能量消耗，并有所改善 胰岛素敏感性，支持STAT1在年龄相关的fTreg功能障碍、TCN炎症和 肥胖症。在这一应用中，我们建议进一步研究T细胞的作用和机制，包括TCN和 FTreg在年龄相关的炎症和代谢功能中有三个目标：Aim 1将研究TCN(直接驱动程序)如何 炎症)有助于AT炎症和代谢功能随年龄增长和组织培养； AIM 2将研究Treg(炎症调节因子)如何影响AT的炎症和代谢功能 随着小鼠年龄的增长；目标3将检查饮食和药物抑制STAT1途径对 小鼠年龄相关的fTreg功能、炎症和代谢功能。产生了几个新的小鼠模型 在Pi‘s实验室和人类AT标本中，用流式细胞术、定量PCR、RNA-Seq、全身和组织... 将使用特定的代谢分析和其他技术。我们的建议旨在揭示T细胞，包括 Tcn和fTreg参与了AT的炎症和代谢功能，并可能有助于开发新的 减轻与年龄相关的炎症和预防随年龄增长的代谢性疾病的治疗方法。