The effects of bariatric surgery on the endoplasmic reticulum stress pathway in human adipose tissue
Philip Voyias1, Ciara McCarthy1, Adaikala Antonysunil1, Warunee Kumasaiyai1, Fadi Al Naji1, Kirsty McGee1, Alison Harte1, Ponnusamy Saravanan2, Ioannis Kyrou1, Philip McTernan1 & Gyanendra Tripathi1
Background: Endoplasmic reticulum (ER) stress 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. It induces an unfolded protein response (UPR) to restore functional integrity which leads to upregulation of three master regulators of ER; PKR-like ER-regulated kinase (PERK), inositol requiring enzyme1α (IRE1α) and activating transcription factor6 (ATF6), in addition to protein chaperones. The aim of this study was to examine whether restrictive or malabsorptive bariatric surgery in obese women with T2DM leads to reduction in ER stress.
Methods: Abdominal subcutaneous (AbSc) AT was isolated from 12 Caucasian women aged 3860 yrs with T2DM and BMI >35 kg/m2, that had undergone restrictive or/malabsorptive bariatric surgery. Biopsies were collected at the time of surgery and 30 days post-surgery. AbSc AT from two control groups of non-diabetic females were also included; overweight/obese, n=11; BMI≥27.5 kg/m2, aged 3560 and lean, n=6; BMI≤25.0 kg/m2 aged 4050. Expression of key ER stress markers were measured by qRT-PCR.
Results: The expression of ER stress markers IRE1α, ATF6, Grp78/BIP, ATF4, and PDI, were significantly increased in AbSc AT from overweight/obese compared to lean subjects (n=17; P<0.01). The expression of ER stress markers in T2DM patients changed significantly following bariatric surgery and varied with the type of operation. Four bariatric patients showed a reduction in all ER stress markers tested (IRE1α, ATF6, Grp78/BiP, ATF4, PDI, and DDIT3), whilst the remaining patients showed selective improvement.
Conclusion: Our findings indicate overweight/obese subjects have elevated ER stress in AbSc AT compared to lean. Subsequent to bariatric surgery, in T2DM patients, a down-regulation in various ER stress markers was observed, although most patients showed a reduction in one or two of the three key pathways. Future studies examining ER stress following 15% weight-loss are planned.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.