Unfolded protein response in adipose tissue of obese diabetic women significantly improved 6 months post bariatric surgery, irrespective of malabsorptive or bypass operation type and correlates with plasma glucose concentration

Abstract

In obesity, excess nutrients and an increased demand for protein synthesis contribute to unfolded proteins accumulating within the endoplasmic reticulum and consequent activation of unfolded protein response (UPR). UPR in adipose tissue (AT) is critical to the initiation and integration of inflammation and insulin signalling pathways in obese and type 2 diabetes mellitus (T2DM) patients. The aim of this study was to examine whether novel malabsorptive or bypass bariatric surgery in obese women with T2DM leads to reduction in UPR. Abdominal subcutaneous (AbSc) AT was isolated from 30 Caucasian obese T2DM women aged 54.1±1.3 (mean±S.E.M.) years, BMI 41.21±1.0 kg/m2, that had undergone bariatric surgery of malabsorptive; gastric band (n=9) or novel gastric plication (n=13), or bypass; biliopancreatic diversion (n=8) type. Biopsies and anthropometric data were collected at the time of surgery and 6 months post-surgery. UPR markers were measured by qRT-PCR and western blotting and correlation analysis was performed. Six months post-operation all subjects significantly reduced body weight (P<0.001) with mean excess BMI lost 33.4±2.4%. Anthropometric measurements were significantly improved; fat mass, HbA1c, glucose, insulin, HOMA-IR, and total cholesterol (all P<0.001). ATF6, IRE1α, XBP1s, ATF4, and CHOP10 mRNAs and ATF6, pIRE1α, XBP1s, Calnexin and Bip proteins were all significantly (P<0.05) reduced post-surgery irrespective of operation type. Correlations between UPR mRNAs were strengthened post-surgery for ATF4 and CHOP10 (P=0.041–P<0.001) and IRE1α and ATF6 (P=0.853–P<0.001). Post-surgery plasma glucose correlated significantly (P=0.034) with XBP1s mRNA. This study highlights that bariatric surgery induced weight loss is coupled with improved glucose homeostasis and reduced UPR expression in AT. Furthermore post weight loss there are enhanced associations identified between UPR and XBP1 in AT and plasma glucose which may arise due to improved glucose homeostasis. This suggests UPR regulation in AT is linked to plasma glucose levels which aligns to metabolic health.