Mechanisms of impaired pancreatic β-cell function in high-fat diet-induced obese mice: The role of endoplasmic reticulum stress

The aim of the study was to examine whether there was excessive endoplasmic reticulum stress (ERs) in the islets of high-fat diet (HFD)-induced obese mice, as well as the effects of ERs on β-cell function. Male C57BL/6J mice were fed a HFD for 16 weeks. Pancreatic β-cell function was evaluated using intraperitoneal glucose tolerance and insulin release tests, and via electron microscopy. The expression of activating transcription factor 6 (ATF6) and phosphorylated (p)-eukaryotic initiation factor 2α (eIF2α) were detected via immunofluorescence staining to determine whether exposure to a HFD induced ERs in pancreatic islets. In vitro, ERs was induced by palmitate (PA) in INS-1 cells, and the protein expression of ATF6, and mRNA expression of ATF6 and insulin were examined via western blot and quantitative PCR (qPCR) analyses, respectively. The nuclear localization of ATF6 was examined by immunofluorescence. Finally, small interfering (si)RNA was used to downregulate ATF6 expression in INS-1 cells to further determine whether ATF6 mediated the ERs-induced impairment of insulin gene transcription. After 16 weeks of induction, the obese mice showed impaired glucose tolerance, insulin resistance and hyperinsulinemia. Immunohistochemistry staining showed increased p-eIF2α and ATF6 expression in pancreatic islets in the obesity group compared with the normal group. Electron microscopy indicated that the microstructures and secretory functions of β-cells were impaired. After 24 h of incubation, ATF mRNA and protein expression in the PA group was significantly higher compared with the control group. However, the insulin mRNA expression in the PA group was significantly decreased. Furthermore, qPCR showed that the insulin mRNA expression was significantly increased 24 h after PA treatment in cells transfected with ATF6-siRNA compared with the negative control group. The present suggested shows that ERs-induced activation of ATF6 may play an important role in the development of β-cell dysfunction in obese mice.