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.

项目概要 衰老的特点是慢性、低度炎症，被称为“炎症”。与衰老类似， 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 最终，与瘦弱和年老的同龄人相比，他们患上了糖尿病。脂肪组织与炎症和 肥胖会导致胰岛素抵抗的发展。丝裂原激活蛋白激酶 (MAPK) 家族可以 促进脂肪细胞胰岛素抵抗并促进/加剧脂肪细胞炎症。例如， MAPK（细胞外信号调节蛋白激酶 1/2 (ERK1/2)）的磷酸化可抑制胰岛素信号传导 并诱导炎症基因表达。然而，目前尚不清楚 MAPKs 如何因应 脂肪组织炎症以及 MAPK 失活对于补偿和防止衰老至关重要- 在瘦人和肥胖人群中诱导胰岛素抵抗。 MAPK 的失活对于体内稳态至关重要 为了维持脂肪组织功能，而失活的丧失可能会放大 MAPK pro- 驱动代谢疾病进展的炎症信号。因此，迫切需要了解 MAPK 失活的分子基础，引发并加剧炎症和肥胖，以便识别 在永久表型之前治疗亚临床衰老进展的潜在治疗靶点 糖尿病明显。该项目测试了以下假设：双特异性磷酸酶 5 (DUSP5) 是一种关键的酶 核 ERK1/2 信号传导失活剂，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，特别是与肥胖相关时。该提案制定了两个目标 来检验这个假设。目标1，将检验DUSP5敲除小鼠炎症加重的假设， 老年小鼠与瘦小鼠的胰岛素抵抗和 ERK1/2 激活。目标 2，将检验假设 肥胖会加剧 DUSP5 敲除小鼠中衰老引起的炎症和胰岛素抵抗。这个提议 将强调磷酸酶（特别是 DUSP5）在脂肪细胞生物学中的新兴作用，并提供新的 深入了解与胰岛素抵抗相关的脂肪组织炎症和肥胖的控制。