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Title: The impact of human adipose tissue on metabolic dysfunction in obesity and type 2 diabetes mellitus
Author: Kumsaiyai, Warunee
ISNI:       0000 0004 5359 6290
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2014
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This thesis sought to investigate how systemic lipids may contribute to the adipocyte derived inflammatory response and highlight how the adipocyte’s function can alter in different metabolic states which could contribute to the pathogenesis of type 2 diabetes mellitus (T2DM) and cardiovascular risk. Specifically, this thesis firstly examined the inflammatory nature of lipoprotein-associated phospholipase A2 (LpPLA2), a member of the phospholipase A2 super family of enzymes which previously has been shown to enhance Ox-LDL production in foam cells during arterial inflammation contributing to coronary artery disease. Therefore initial studies sought to (1) characterise PLA2 isoforms in lean, obese, T2DM abdominal subcutaneous (AbdSc) and omental (Om) in human adipose tissue (AT); (2) evaluate the role of lipids and inflammatory markers on circulating LpPLA2, and (3) determine the in vitro regulation of LpPLA2 in human adipocytes by its influence on LDL and Ox-LDL. AT and sera from lean, overweight, obese and T2DM subjects were taken. PLA2 gene expression was determined by microarray, RT-PCR and Western Blot. Associations between circulating LpPLA2 and metabolic parameters were investigated. The human adipocyte cell line, Chub-S7, was used to assess the effects of oxidized LDL (Ox-LDL) and LDL on PLA2 expression. LpPLA2 mRNA levels were higher in AbdSc AT than Om AT in obesity by 2-fold (P<0.05). The cPLA2 protein expression increased with obesity in AbdSc AT (P<0.01). T2DM showed increased LpPLA2 mRNA levels in AbdSc (P<0.001) and Om AT (P<0.01). Serum LpPLA2 showed positive correlations with cholesterol, TG, LDL, endotoxin and Ox-LDL (P<0.001) in non-diabetic subjects and with Ox-LDL (P<0.001), LDL (P<0.01) and cholesterol (P<0.05) in T2DM. In differentiated pre-adipocytes, activation of LpPLA2 protein expression was noted in response to LDL and Ox-LDL (P<0.001). The adipocyte appeared to be an active source of LpPLA2, altered by fat depot and metabolic state, with LpPLA2 protein expression induced by LDL and Ox-LDL, in vitro. Increased LpPLA2 protein from the adipocyte in obesity and/or T2DM could contribute to raise circulating Ox-LDL, as noted in other studies as well with increasing adiposity, which promotes further inflammation and atherosclerotic risk. Through the development of these current studies it appeared that how the adipocyte managed lipids was important to how the adipocyte may induce an inflammatory response and pathogenic factors. Therefore subsequent studies investigated how the change in metabolic state such as those derived in T2DM patients that undergo bariatric surgery may not necessarily reverse their inflammatory response. Previous studies from the team have shown that lipids may induce an innate immune response via toll like receptor (TLR) activation therefore subsequent investigations sought to consider the potential role of triglycerides (TG) as another mediator of inflammation. As such studies examined the specific 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. Serum and AT was taken from a cohort of Obese, T2DM, female subjects prior to bariatric surgery and 6 months post-surgery. Human differentiated pre-adipocyte Chub S7 cells were again 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 TLR-4 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). Whilst the in vitro treatment of differentiated Chub S7 cells highlighted VLDL induced TLR 4 mRNA expression (P<0.05) suggesting the inflammatory impact of lipids on adipocytes. These studies further highlighted that the reduction in AT inflammation appears dependent on how successfully subjects reduce their serum triglyceride, which appears supported by the in vitro findings. 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. Taken together, these studies and thesis highlight the diverse nature of lipids and their interaction with the adipocyte to impact on their inflammatory response. These data also highlight the importance to maintain a good systemic lipid profile low in TG to reduce adipocyte induced inflammation and that AT may represent an important therapeutic target to reduce inflammation, atherosclerotic risk and development of metabolic complications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology ; RC Internal medicine