Service of Endocrinology. University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain.
Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
Int J Obes (Lond). 2017 Oct;41(10):1556-1563. doi: 10.1038/ijo.2017.147. Epub 2017 Jun 20.
Oxidative stress and inflammation are related to obesity, but the influence of metabolic disturbances on these parameters and their relationship with endoplasmic reticulum (ER) stress is unknown. Therefore, this study was performed to evaluate whether metabolic profile influences ER and oxidative stress in an obese population with/without comorbidities.
A total of 113 obese patients were enrolled in the study; 29 were metabolically healthy (MHO), 53 were metabolically abnormal (MAO) and 31 had type 2 diabetes (MADO). We assessed metabolic parameters, proinflammatory cytokines (TNFα and IL-6), mitochondrial and total reactive oxygen species (ROS) production, glutathione levels, antioxidant enzymes activity, total antioxidant status, mitochondrial membrane potential and ER stress marker expression levels (glucose-regulated protein (GRP78), spliced X-box binding protein 1 (XBP1), P-subunit 1 alpha (P-eIF2α) and activating transcription factor 6 (ATF6).
The MAO and MADO groups showed higher blood pressure, atherogenic dyslipidemia, insulin resistance and inflammatory profile than that of MHO subjects. Total and mitochondrial ROS production was enhanced in MAO and MADO patients, and mitochondrial membrane potential and catalase activity differed significantly between the MADO and MHO groups. In addition, decreases in glutathione levels and superoxide dismutase activity were observed in the MADO vs MAO and MHO groups. GRP78 and CHOP protein and gene expression were higher in the MAO and MADO groups with respect to MHO subjects, and sXBP1 gene expression was associated with the presence of diabetes. Furthermore, MAO patients exhibited higher levels of ATF6 than their MHO counterparts. Waist circumference was positively correlated with ATF6 and GRP78, and A1c was positively correlated with P-Eif2α. Interestingly, CHOP was positively correlated with TNFα and total ROS production and GRP78 was negatively correlated with glutathione levels.
Our findings support the hypothesis that both inflammation and oxidative stress are involved in the induction of ER stress signaling pathways in the leukocytes of metabolically unhealthy obese vs healthy obese subjects.
氧化应激和炎症与肥胖有关，但代谢紊乱对这些参数的影响及其与内质网（ER）应激的关系尚不清楚。因此，本研究旨在评估代谢谱是否会影响肥胖人群（伴或不伴合并症）的 ER 和氧化应激。
共纳入 113 名肥胖患者；其中 29 名代谢健康（MHO），53 名代谢异常（MAO），31 名患有 2 型糖尿病（MADO）。我们评估了代谢参数、促炎细胞因子（TNFα 和 IL-6）、线粒体和总活性氧（ROS）产生、谷胱甘肽水平、抗氧化酶活性、总抗氧化状态、线粒体膜电位和 ER 应激标志物表达水平（葡萄糖调节蛋白（GRP78）、剪接 X 盒结合蛋白 1（XBP1）、P 亚单位 1α（P-eIF2α）和激活转录因子 6（ATF6）。
MAO 和 MADO 组的血压、动脉粥样硬化性血脂异常、胰岛素抵抗和炎症谱均高于 MHO 组。MAO 和 MADO 患者的总 ROS 和线粒体 ROS 产生增加，MADO 组与 MHO 组之间的线粒体膜电位和过氧化氢酶活性差异显著。此外，MADO 组的谷胱甘肽水平和超氧化物歧化酶活性下降。与 MHO 组相比，MAO 和 MADO 组的 GRP78 和 CHOP 蛋白和基因表达均升高，sXBP1 基因表达与糖尿病的存在相关。此外，MAO 患者的 ATF6 水平高于 MHO 患者。腰围与 ATF6 和 GRP78 呈正相关，A1c 与 P-Eif2α 呈正相关。有趣的是，CHOP 与 TNFα 和总 ROS 产生呈正相关，而 GRP78 与谷胱甘肽水平呈负相关。
我们的研究结果支持这样一种假设，即炎症和氧化应激都参与了代谢不健康的肥胖与健康肥胖受试者白细胞中内质网应激信号通路的诱导。
