ER stress mediates mitochondrial dysfunction in human adipocytes which is exacerbated in obesity

L. Jackisch, L. Escalera, A. Murphy, P. McTernan, H. Randeva, G. Tripathi
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Abstract

The pathogenesis of obesity and T2DM mediates mitochondrial dysfunction which, in part, may arise as a consequence of endoplasmic reticulum stress (ERS). Therefore, we investigated whether induction of ERS contributes to mitochondrial dysfunction in human adipocytes. Chronic ERS was induced in post-differentiated human adipocyte cell line (Chub-S7) and primary lean and obese abdominal subcutaneous adipocytes (AbdSc Ad) using 0.25μg/ml and 0.75μg/ml tunicamycin. Key parameters of mitochondrial function were determined, including oxygen consumption rate (OCR), ATP concentration, mitochondrial membrane potential (MMP), mitochondrial number and dynamics. We observed dose-dependent increases of OCR in Chub-S7 adipocytes following treatment with Tn (p<0.01). This was accompanied by decreased elongation (16%↓P<0.05), decreased cellular area occupied by mitochondria (28%↓P<0.05), and no change to mitochondrial number, as observed by confocal microscopy. Moreover, MMP was significantly compromised (32%↓P=0.0001), whilst ATP levels were not affected. Consistent with increasing OCR levels in the cellular model, primary adipocytes from lean subjects revealed higher levels of OCR with Tn treatment, potentially as a mechanism to compensate for cellular stress; whereas, mitochondria from obese subjects displayed impaired respiratory function. In summary, these human data suggest that mitochondrial dysfunction occurs more readily in response to ERS, in adipocytes from obese subjects than their lean counterparts.
内质网应激介导人脂肪细胞的线粒体功能障碍,而这种功能障碍在肥胖中加剧
肥胖和2型糖尿病的发病机制介导线粒体功能障碍,这在一定程度上可能是内质网应激(ERS)的结果。因此,我们研究了ERS的诱导是否有助于人类脂肪细胞的线粒体功能障碍。用0.25μg/ml和0.75μg/ml的tunicamycin诱导分化后的人脂肪细胞系Chub-S7和原发性肥胖腹部皮下脂肪细胞(AbdSc Ad)产生慢性ERS。测定线粒体功能的关键参数,包括耗氧率(OCR)、ATP浓度、线粒体膜电位(MMP)、线粒体数量和动力学。我们观察到Tn治疗后Chub-S7脂肪细胞OCR呈剂量依赖性增加(p<0.01)。共聚焦显微镜观察到,线粒体的延伸率降低(16%↓P<0.05),线粒体占据的细胞面积减少(28%↓P<0.05),线粒体数量没有变化。此外,MMP显著受损(32%↓P=0.0001),而ATP水平未受影响。与细胞模型中增加的OCR水平一致,来自瘦弱受试者的原代脂肪细胞在Tn处理下显示出更高的OCR水平,这可能是一种补偿细胞应激的机制;然而,肥胖受试者的线粒体显示出呼吸功能受损。总之,这些人类数据表明,肥胖受试者的脂肪细胞比瘦受试者的脂肪细胞更容易发生线粒体功能障碍。
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