A role for DUSP5 in aging and obesity

项目总结 衰老的特点是慢性低度炎症，已被称为“炎症”。与衰老相似， 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 最终与他们瘦弱和年迈的同龄人相比，他们患有糖尿病。脂肪组织与发炎和 肥胖导致胰岛素抵抗的发展。丝裂原活化蛋白激酶(MAPK)家族可以 促进脂肪细胞胰岛素抵抗，促进/加剧脂肪细胞炎症。例如, 细胞外信号调节蛋白激酶1/2(ERK1/2)的磷酸化抑制胰岛素信号转导 并诱导炎症基因表达。然而，目前尚不清楚MAPK是如何被停用以应对 脂肪组织炎症，如果MAPK失活对补偿和防止衰老至关重要- 在瘦和肥胖人群中诱导胰岛素抵抗。MAPKs的失活对脑内环境的稳定至关重要 以维持脂肪组织的功能，而失活可能会放大MAPK的前体- 推动代谢性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，启动和助长炎症和肥胖，以便识别 潜在的治疗靶点在永久性表型之前治疗亚临床衰老的进展 糖尿病的表现。这个项目测试了双特异性磷酸酶5(DUSP5)是一个关键的 核内ERK1/2信号失活物作为反馈抑制物抑制炎症诱导的胰岛素 脂肪组织中的抵抗力，特别是与肥胖有关的时候。这项建议有两个目的 来检验这一假设。目的1，将检验DUSP5基因敲除小鼠加剧炎症的假设， 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 肥胖加剧了DUSP5基因敲除小鼠衰老引起的炎症和胰岛素抵抗。这项建议 将强调磷酸酶，特别是DUSP5在脂肪细胞生物学中的新作用，并提供新的 对控制脂肪组织发炎和肥胖的见解与胰岛素抵抗有关。

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.