Bariatric surgery can acutely modulate ER-stress and inflammation on subcutaneous adipose tissue in non-diabetic patients with obesity

Abstract

Background Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is the most effective and durable treatment option for severe obesity. The mechanisms involving adipose tissue may be important to explain the effects of surgery. Methods We aimed to identify the genetic signatures of adipose tissue in patients undergoing RYGB. We evaluated 13 obese, non-diabetic patients (mean age 37 years, 100% women, Body mass index (BMI) 42.2 kg/m2) one day before surgery, 3 and 6 months (M) after RYGB. Results Analysis of gene expression in adipose tissue collected at surgery compared with samples collected at 3 M and 6 M Post-RYGB showed that interleukins [Interleukin 6, Tumor necrosis factor-α (TNF-α), and Monocyte chemoattractant protein-1(MCP1)] and endoplasmic reticulum stress (ERS) genes [Eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) and Calreticulin (CALR)] decreased during the follow-up (P ≤ 0.01 for all). Otherwise, genes involved in energy homeostasis [Adiponectin and AMP-activated protein kinase (AMPK)], cellular response to oxidative stress [Sirtuin 1, Sirtuin 3, and Nuclear factor erythroid 2-related factor 2 (NRF2)], mitochondrial biogenesis [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)] and amino acids metabolism [General control nonderepressible 2 (GCN2)] increased from baseline to all other time points evaluated (P ≤ 0.01 for all). Also, expression of Peroxisome proliferator-activated receptor gamma (PPARϒ) (adipogenesis regulation) was significantly decreased after RYGB (P < 0.05). Additionally, we observed that PGC1α, SIRT1 and AMPK strongly correlated to BMI at 3 M (P ≤ 0.01 for all), as well as ADIPOQ and SIRT1 to BMI at 6 M (P ≤ 0.01 for all). Conclusions Our findings demonstrate that weight loss is associated with amelioration of inflammation and ERS and increased protection against oxidative stress in adipose tissue. These observations are strongly correlated with a decrease in BMI and essential genes that control cellular energy homeostasis, suggesting an adaptive process on a gene expression level during the caloric restriction and weight loss period after RYGB. Trial registration CAAE: 73,585,317.0.0000.5440

Roux-en-Y Gastric Bypass Modulates AMPK, Autophagy and Inflammatory Response in Leukocytes of Obese Patients

“…Moreover, Gregor et al [ 18 ] reported reduced expression of ER stress markers in the liver (glucose-regulated protein 78 kDa (GRP78), phosphorylated eukaryotic translation initiation factor 2A (p-EIF2α)), subcutaneous adipose tissue (X-box binding protein 1 (sXBP1), GRP78, CHOP and p-EIF2α) one year after RYGB intervention. In line with this, Ferraz Bannitz et al [ 19 ] observed a drop in ER stress expression (PERK and calreticulin(CALR)) in subcutaneous adipose tissue 3–6 months after surgery. Both studies described changes mainly in transcripts in subcutaneous adipose tissue; as far as we are aware, we are the first group to describe the effects of RYGB on ER stress protein markers in leukocytes.…”

“…However, only a few studies have evaluated the effect of bariatric surgery on AMPK in humans. Increased expression and activity of AMPK was reported in subcutaneous adipose tissue 3–6 months after RYGB, and was accompanied by a reduction in oxidative stress, ER stress and inflammatory markers [ 19 , 38 ]. Similarly, AMPK activity was found to be increased in PBMCs one year after bariatric surgery—via laparoscopic bypass or sleeve gastrectomy—inducing chaperone-mediated autophagy, a reduction in protein oxidative damage and hsCRP [ 39 , 40 ].…”

“…However, persistent activation of UPR pathways during metabolic overload can lead to pathological events, including impairment of insulin signaling, initiation of inflammatory cascades [ 15 ], or even expression of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a transcription factor involved in the modulation of numerous pro-apoptotic factors [ 16 , 17 ]. In this context, it has been reported that ER stress is reduced in the adipose tissue of obese subjects after bariatric surgery, suggesting an association between ER stress relief and metabolic improvements in these patients [ 18 , 19 ].…”

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

“…Furthermore, an ovariectomized menopausal mouse model shows that Nrf2 KO gain more bodyweight than control mice [ 117 ]. In humans, it is noteworthy that obese patients undergoing Roux-en-Y gastric bypass show elevated expression of Nrf2 in adipose tissue after surgery [ 118 ]. Taken together, these results suggest that Nrf2 in adipose tissue has a beneficial effect on obesity-related insulin resistance.…”

The Mechanisms and Management of Age-Related Oxidative Stress in Male Hypogonadism Associated with Non-communicable Chronic Disease

“…In 2017, a study conducted on 47 men with morbid obesity reported a significant decrease in the salivary oxidative markers (levels of lipid peroxidation, oxidation protein products, and 8-hydroxy-D-guanosine) six months after bariatric surgery [ 149 ]. Three months after gastric bypass, the gene expression profiles of obese nondiabetic patients were also reportedly altered, with an increased expression in the genes (SOD2, Sirtuin 1, Sirtuin 3, and Nuclear factor erythroid 2-related factor 2) involved in the cellular response to oxidative stress [ 150 ]. Weight loss in bariatric surgery improves the total antioxidant capacity, which correlates with an improvement in the BMI, waist-to-hip circumference, serum insulin, and uric acid [ 147 ].…”