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

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.