A role for DUSP5 in aging and obesity

DUSP5 在衰老和肥胖中的作用

• 批准号: 10430694
• 负责人: Bradley S Ferguson
• 金额: $ 21.72万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430694
• 关键词: 1 year old; Adipocytes; Adipose tissue; Age; Aging; Attenuated; Back; Cardiovascular Diseases; Chronic; Data; Development; Diabetes Mellitus; Disease Progression; Elderly; Family; Feedback; Feeds; Gene Expression; Genes; Genetic; Health; Heart Diseases; Homeostasis; Human; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Knock-out; Knockout Mice; Lead; Link; LoxP-flanked allele; MAPK8 gene; Metabolic Diseases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Nuclear; Obese Mice; Obesity; Pathology; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Population; Process; Protein Dephosphorylation; Protein Kinase; Public Health; Publishing; Reporting; Role; Signal Transduction; Specificity; TNF gene; Testing; Thinness; Work; adipocyte biology; adipocyte differentiation; adult obesity; aged; base; extracellular; factor A; high risk; human old age (65+); inhibitor; insight; insulin signaling; middle age; new therapeutic target; obese person; p38 Mitogen Activated Protein Kinase; response; therapeutic target

PROJECT SUMMARY Aging is characterized by chronic, low-grade inflammation that has been termed “Inflammaging.” Similar to aging, obesity is linked to chronic inflammation and older obese adults are at higher risk for developing insulin resistance and ultimately diabetes compared to their lean and aged counterparts. Adipose tissue links inflammaging and obesity to the development of insulin resistance. The mitogen-activated protein kinase (MAPK) family can promote adipocyte insulin resistance and promote/exacerbate adipocyte inflammation. For instance, phosphorylation of the MAPK, extracellular signal-regulated protein kinase 1/2 (ERK1/2), inhibits insulin signaling and induces inflammatory gene expression. However, it is unclear how MAPKs are deactivated in response to adipose tissue inflammation and if MAPK deactivation is critical to compensate and protect against aging- induced insulin resistance in lean vs obese populations. Deactivation of MAPKs is critical for homeostasis in order to maintain adipose tissue function, whereas loss of deactivation potentially amplifies MAPK pro- inflammatory signals that drives metabolic disease progression. Thus, there is a critical need to understand the molecular underpinnings for MAPK deactivation that initiate and fuel inflammaging and obesity in order to identify potential therapeutic targets to treat the progression of subclinical aging before permanent phenotypes like diabetes manifest. This project tests the hypothesis that that dual-specificity phosphatase 5 (DUSP5) is a critical deactivator of nuclear ERK1/2 signaling that serves as a feedback inhibitor to limit Inflammaging-induced insulin resistance in adipose tissue, particularly when linked to obesity. Two aims have been devloped in this proposal to test this postulate. Aim 1, will test the hypothesis that DUSP5 knockout mice have aggravated inflammation, insulin resistance and ERK1/2 activation in aged mice vs. lean counterparts. Aim 2, will test the hypothesis that obesity exacerbates aging-induced inflammation and insulin resistance in DUSP5 knockout mice. This proposal will highlight an emerging role for phosphatases, particularly DUSP5, in adipocyte biology and provide new insights into the control of adipose tissue inflammaging and obesity linked insulin resistance.

项目摘要 衰老的特征是慢性、低度炎症，称为“炎症”。与衰老相似， 肥胖与慢性炎症有关，老年肥胖者患胰岛素抵抗的风险更高 与瘦弱的老年人相比，最终会患上糖尿病。脂肪组织连接炎症和 肥胖与胰岛素抵抗的关系丝裂原活化蛋白激酶（MAPK）家族可 促进脂肪细胞胰岛素抵抗和促进/加重脂肪细胞炎症。比如说， MAPK（细胞外信号调节蛋白激酶1/2（ERK 1/2））的磷酸化抑制胰岛素信号传导 并诱导炎症基因表达。然而，目前还不清楚MAPK是如何响应于 脂肪组织炎症，如果MAPK失活是至关重要的，以补偿和保护免受老化- 在瘦人群与肥胖人群中诱导胰岛素抵抗。MAPKs的失活对于体内稳态至关重要， 以维持脂肪组织的功能，而失活的损失可能会放大MAPK的促增殖作用。 炎症信号驱动代谢疾病进展。因此，迫切需要了解 MAPK失活的分子基础，启动和燃料炎症和肥胖，以确定 潜在的治疗目标，以治疗亚临床衰老的进展之前，永久表型， 糖尿病患者该项目测试的假设，即双特异性磷酸酶5（DUSP 5）是一个关键的 核ERK 1/2信号转导的失活剂，作为反馈抑制剂限制炎症诱导的胰岛素 脂肪组织的抵抗力，特别是与肥胖有关的抵抗力。这个建议有两个目的 来验证这个假设目的1，将检验DUSP 5敲除小鼠炎症加重的假设， 胰岛素抵抗和ERK 1/2活化。目标2，将检验假设， 肥胖加剧了DUSP 5敲除小鼠中衰老诱导的炎症和胰岛素抵抗。这项建议 将强调磷酸酶，特别是DUSP 5在脂肪细胞生物学中的新兴作用，并提供新的 对控制脂肪组织炎症和肥胖相关的胰岛素抵抗的见解。