A role for DUSP5 in aging and obesity

DUSP5 在衰老和肥胖中的作用

• 批准号: 10625471
• 负责人: Bradley S Ferguson
• 金额: $ 18.16万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625471
• 关键词: 1 year old; Adipocytes; Adipose tissue; Age; Aging; Attenuated; Back; Cardiovascular Diseases; Chronic; Compensation; Data; Development; Diabetes Mellitus; Disease Progression; Elderly; Equilibrium; Extracellular Signal Regulated Kinases; Family; Feedback; Feeds; Gene Expression; Genes; Genetic; Health; Heart Diseases; Homeostasis; Human; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Knock-out; Knockout Mice; 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; extracellular; 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”。类似于衰老， 肥胖与慢性炎症有关，老年肥胖成年人患胰岛素抵抗的风险更高 最终与糖尿病与瘦身和老化的糖尿病相比。脂肪组织连接炎症和 肥胖，胰岛素抵抗的发展。有丝分裂原激活的蛋白激酶（MAPK）家族可以 促进脂肪细胞胰岛素抵抗并促进/加剧脂肪细胞注射。例如， MAPK，细胞外信号调节的蛋白激酶1/2（ERK1/2）的磷酸化抑制胰岛素信号传导 并诱导炎症基因表达。但是，尚不清楚如何响应于MAPK 脂肪组织注射和MAPK停用对于补偿和防止衰老至关重要 瘦肉与肥胖种群中诱导的胰岛素抵抗。 MAPK的停用对体内平衡至关重要 为了维持脂肪组织功能 驱动代谢疾病进展的炎症信号。那是迫切需要了解 启动和燃料发炎和肥胖以识别的MAPK停用的分子基础 在永久表型之前，潜在的治疗靶标治疗亚临床老化的进展 糖尿病表现出来。该项目检验了以下假设：双特异性磷酸酶5（DUSP5）是关键 核ERK1/2信号的取消活力，该信号传导可作为反馈抑制剂，以限制炎症诱导的胰岛素 脂肪组织的耐药性，尤其是与肥胖有关的抗性。该提案中已有两个目标 测试这个假设。 AIM 1，将检验DUSP5敲除小鼠的假设，汇总注射， 老年小鼠与瘦小对应物中的胰岛素耐药性和ERK1/2激活。 AIM 2将检验以下假设 肥胖症加剧了DUSP5敲除小鼠衰老引起的炎症和胰岛素抵抗。这个建议 将突出磷酸酶，尤其是DUSP5的新兴作用，在脂肪细胞生物学中，并提供新的作用 洞察脂肪组织炎症和肥胖连接胰岛素抵抗的洞察力。