Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity
Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity
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DOI：
10.1089/ars.2014.5939
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发表时间：
2015-09-01
影响因子：
6.6
通讯作者：
Malagon, Maria M.
中科院分区：
文献类型：
--
作者：
Diaz-Ruiz, Alberto;Guzman-Ruiz, Rocio;Malagon, Maria M.
目的：肥胖症的特征在于低级别的全身炎症状态和脂肪组织（AT）功能障碍，其使个体易于发展胰岛素抵抗（IR）和代谢疾病。然而，肥胖个体的子集，称为代谢健康肥胖（MHO）个体，被保护免于肥胖相关的代谢异常。在这里，我们的目的是确定分子因子和途径的脂肪细胞，负责从胰岛素敏感的胰岛素抵抗，代谢不健康的肥胖（MUHO）表型的进展。结果如下：对来自皮下（SC）和网膜（OM）人类AT的脂肪细胞配对样本的蛋白质组学分析显示，这两种类型的细胞在MUHO状态下都发生了改变。具体而言，谷胱甘肽氧化还原循环和其他抗氧化防御系统以及蛋白质折叠机制失调，内质网应激增加，在脂肪细胞从IR科目。此外，蛋白酶体活性也受到损害的脂肪细胞的MUHO个人，这是与增强积累的氧化和泛素化蛋白在这些细胞。蛋白酶体活性也受损的脂肪细胞的饮食诱导的肥胖小鼠和3 T3-L1脂肪细胞暴露于棕榈酸酯。与这些数据一致，蛋白酶体抑制显著损害3 T3-L1脂肪细胞中的胰岛素信号传导。创新：这项研究提供了第一个证据的发生蛋白质稳态失调的脂肪细胞在人类肥胖，这与氧化损伤，干扰胰岛素信号在这些细胞。结论：我们的研究结果表明，蛋白酶体功能障碍和受损的脂肪细胞中的蛋白稳态，导致蛋白质氧化和/或错误折叠，构成主要的致病机制，在IR的发展肥胖。抗氧化剂。氧化还原信号。23，597-612。
Aims: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. Results: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. Innovation: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. Conclusion: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity. Antioxid. Redox Signal. 23, 597-612.