Differential unfolded protein response in skeletal muscle from non-diabetic glucose tolerant or intolerant patients with obesity before and after bariatric surgery.

Abstract

Not all people with obesity become glucose intolerant, suggesting differential activation of cellular pathways. The unfolded protein response (UPR) may contribute to the development of insulin resistance in several organs, but its role in skeletal muscle remains debated. Therefore, we explored the UPR activation in muscle from non-diabetic glucose tolerant or intolerant patients with obesity and the impact of bariatric procedures. Muscle biopsies from 22 normoglycemic (NG, blood glucose measured 120min after an oral glucose tolerance test, G120 < 7.8mM) and 22 glucose intolerant (GI, G120 between 7.8 and 11.1mM) patients with obesitywere used to measure UPR activation by RTqPCR and western blot. Then, UPR was studied in biopsies from 7 NG and 7 GI patients before and 1year after bariatric surgery. Binding immunoglobulin protein (BIP) protein was ~ 40% higher in the GI compared to NG subjects. Contrastingly, expression of the UPR-related genes BIP, activating transcription factor 6 (ATF6) and unspliced X-box binding protein 1 (XBP1u) were significantly lower and C/EBP homologous protein (CHOP) tended to decrease (p = 0.08) in GI individuals. While BIP protein positively correlated with fasting blood glucose (r = 0.38, p = 0.01), ATF6 and CHOP were associated with G120 (r = - 0.38 and r = - 0.41, p < 0.05) and the Matsuda index (r = 0.37 and r = 0.38, p < 0.05). Bariatric surgery improved metabolic parameters, associated with higher CHOP expression in GI patients, while ATF6 tended to increase (p = 0.08). CHOP and ATF6 expression decreased in non-diabetic GI patients with obesity and was modified by bariatric surgery. These genes may contribute to glucose homeostasis in human skeletal muscle.