Fig 2: Summary of the conclusion. Regarding the present results, a long-term consumption of HFD induces oxidative and ER stress in pancreas, including the islets’ beta cells. Thus, it increases Bip, Chop and Wfs1 mRNA levels in the pancreatic ß cells, which leads to the elevated BIP and CHOP protein amounts in the ER of these cells. Considering the role of WFS1 (a UPR component) in the maintenance of ER homeostasis, the WFS1 protein (the ER resident protein) level also increases in the ER of pancreatic ß cells to restore ER homeostasis. Consequently, other than in the ER, WFS1 protein level decreases in these cells and regarding WFS1 role in insulin biosynthesis and secretion, its reduction would be resulted in the islets’ GSIS and insulin content decrement. Administration of 4-PBA restores all the changes, thus stops the pancreatic islets’ impaired GSIS and insulin content. HFD high-fat diet, ER endoplasmic reticulum, UPR Unfolded protein response.

Fig 3: Effect of high-fat diet and/or 4-PBA on the (A,B) CHOP, (A,C) BIP and (D,E) WFS1 protein levels of the extracted ER of pancreas. Each column represents the mean ± SEM (10 rats/group). **p < 0.01, ****p < 0.0001 versus control of ND group, ####p < 0.0001 versus ND + DMSO group, $$p < 0.01, $$$p < 0.001, $$$$p < 0.0001 versus control of HFD group, ++p < 0.01, +++p < 0.001, ++++p < 0.0001 versus HFD + DMSO group. ND Normal diet, HFD High-fat diet, Crl Control, DMSO Dimethyl Sulfoxide, 4-PBA 4-Phenyl Butyric Acid.

Fig 4: Effect of high-fat diet and/or 4-PBA on the (A,B) CHOP, (A,C) BIP and (A,D) WFS1 protein levels of the pancreas. Each column represents the mean ± SEM (10 rats/group). *p < 0.05, **p < 0.01, ****p < 0.0001 versus control of ND group, ####p < 0.0001 versus ND + DMSO group, $$$p < 0.001, $$$$p < 0.0001 versus control of HFD group, +++p < 0.001, ++++p < 0.0001 versus HFD + DMSO group. ND Normal diet, HFD High-fat diet, Crl Control, DMSO Dimethyl Sulfoxide, 4-PBA 4-Phenyl Butyric Acid.