Systemic triglycerides as a key determinant of TLR regulated inflammatory risk in human adipose tissue post bariatric surgical intervention and weight loss

Bariatric surgery can lead to a quick reversal in type 2 diabetes mellitus (T2DM) status. However, despite this reversal inflammatory responses may still persist via activation of Toll-like receptors (TLR) within adipose tissue (AT); with triglycerides (TGs) noted as a potential mediator of such inflammation. Therefore the aims of these studies were to understand the impact of TG changes, pre- and post-bariatric surgery, on TLR expression in ex vivo AT and the in vitro effects of triglyceride rich lipoprotein (VLDL), on TLR expression in isolated human differentiated pre-adipocytes. Obese, T2DM, female subjects (age: 54.6±6.6 years, BMI pre (41.2±5.5 kg/m2) and 6 months post-surgery (36.05±5.16 kg/m2; n=30) underwent bariatric surgery (banding (n=8); plication (n=14); and biliopancreatic diversion (n=8)). Biochemical data and abdominal subcutaneous AT (AbdSc AT) samples were taken during surgery and 6 months post-surgery. Real-time PCR assessed TLR expression. Human differentiated pre-adipocyte Chub S7 cells were used to examine transcriptional effects of VLDL on TLR expression. Following surgical intervention, BMI (P<0.001), blood glucose (P<0.001), insulin (P<0.001), HOMA-IR (P<0.001), TG (P<0.05), cholesterol (P<0.001), and LDL-cholesterol (P<0.05) were significantly improved. There was a significant reduction in TLR4 mRNA post-surgery (P<0.01) irrespective of surgery type. It was also noted that subjects with the greatest drop (55.5% reduction) in TGs post-surgery (P<0.001) showed a significant correlated reduction in TLR4 mRNA expression (P<0.001). In vitro treatment of differentiated Chub S7 cells highlighted VLDL induced TLR4 mRNA expression (P<0.05).There is a reduction in AT inflammation as denoted by TLR expression. The reduction in AT inflammation appears dependent on how successfully subjects reduce their serum triglyceride, which is supported by in vitro studies. These studies suggest that bariatric surgery lead to metabolic improvement with weight loss, whilst dietary intervention is still required to ensure TGs reduce to reduce inflammation.N/

NFκB as a potent regulator of inflammation in human adipose tissue, influenced by depot, adiposity, T2DM status, and TNFα

Objective Central obesity and sub-clinical inflammation increase metabolic risk, this study examined the intracellular inflammatory pathways in adipose tissue (AT) that contribute to this risk. Design and Methods This study therefore addressed the influence of NFκB and JNK activation in human abdominal subcutaneous (AbdSc) and omental (Om) AT, the effect of adiposity, T2DM status and the role of TNFα in vitro, using molecular biology techniques. Results Our data showed NFκB activity is increased in Om AT versus AbdSc AT (P<0.01), which was reversed with respect to depot specific activation of JNK (P<0.01). However, T2DM status appeared to preferentially activate NFκB (P<0.001) over JNK. Furthermore, in vitro studies showed recombinant human (rh) TNFα treated AbdSc adipocytes increased NFκB activity over time (2-48 h, P<0.05) whilst JNK activity reduced (2 h, 4 h, P<0.05); inhibitor studies supported a preferential role for NFκB as a modulator of TNFα secretion. Conclusions These studies suggest distinct changes in NFκB and JNK activation, dependent upon AT depot, adiposity and T2DM status, with in vitro use of rh TNFα leading to activation of NFκB. Consequently NFκB appears to play a central role in inflammatory mediated metabolic disease over JNK, highlighting NFκB as a potential key target for therapeutic intervention