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Chemical Chaperone PBA Attenuates ER Stress and Upregulates SOCS3 Expression as a Regulator of Leptin Signaling

Burcu Baba1,a, Mursel Caliskan2,b, Gulbahar Boyuk3,c, and Aysun Hacisevki4,d*

1Department of Medical Biochemistry, Faculty of Medicine, Yuksek Ihtisas University, 06520 Ankara, Turkey

2Department of Genetic, Gaziosmanpaşa Hospital, Yeni Yuzyil University, 34245 Istanbul, Turkey

3Department of Physiology, Faculty of Medicine, Ankara Medipol University, 06050 Ankara Turkey

4Department of Biochemistry, Faculty of Pharmacy, Gazi University, 06100 Ankara, Turkey

* To whom correspondence should be addressed.

Received September 8, 2020; Revised December 22, 2020; Accepted December 22, 2020
Endoplasmic reticulum (ER) is very sensitive to the nutritional and energy states of the cells. Disruption of ER homeostasis leads to the accumulation of unfolded/misfolded proteins in the ER lumen, which is defined as ER stress. ER stress triggers the unfolded protein response (UPR). It is suggested that chronic ER stress is associated with obesity and leptin resistance. We investigated the role of ER stress and the effect of the ER stress inhibitor phenylbutyric acid (PBA) of ER stress, in obesity, as well as their impact on leptin signaling. This study involved twenty-four lean and twenty-four leptin-deficient (ob/ob) mice divided into PBA- and vehicle-treated groups. Pancreatic islets were isolated, incubated with leptin for 48 h, and assayed for the expression of CHOP and XBP1s (UPR signaling indicators) and SOCS3 (regulator of leptin signaling) by RT-qPCR. The expression levels of XBP1s and CHOP were markedly increased in the ob/ob controls compared to other groups with and without leptin treatment. No significant differences in the XBP1s and CHOP expression levels were found between the PBA-treated ob/ob and lean mice. SOCS3 expression was significantly upregulated in the PBA-treated ob/ob mice compared to the ob/ob controls after leptin treatment; but no significant difference in the SOCS3 expression was found between the PBA-treated ob/ob and lean mice with and without leptin treatment. Our findings suggested that ER stress plays an important role in the pathology of obesity, while PBA reduces ER stress and may potentially ameliorate leptin signaling.
KEY WORDS: chemical chaperone, endoplasmic reticulum stress, leptin signaling, obesity, phenylbutyric acid, unfolded protein response

DOI: 10.1134/S0006297921040088