A role for DUSP5 in aging and obesity

DUSP5 在衰老和肥胖中的作用

基本信息

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
项目类别：
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

项目摘要

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”。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，与他们瘦弱和衰老的骨骼相比，糖尿病与炎症和衰老有关。肥胖会导致胰岛素抵抗的发生，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。 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，但目前尚不清楚 MAPK 是如何因响应而失活的。脂肪组织炎症以及 MAPK 失活对于补偿和防止衰老至关重要- 与肥胖人群相比，MAPK 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- 因此，迫切需要了解驱动代谢疾病进展的炎症信号。 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该项目测试了双特异性磷酸酶 5 (DUSP5) 是关键的假设。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该提案提出了两个目标。为了测试这一假设，目标 1 将测试 DUSP5 敲除小鼠炎症加剧的假设，老年小鼠与瘦腿小鼠的胰岛素抵抗和 ERK1/2 激活 Aim 2 将检验以下假设：肥胖会加剧 DUSP5 敲除小鼠中衰老引起的炎症和胰岛素抵抗。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。