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Characterisation of circulating extracellular vesicles in human obesity

Witczak, Justyna Karolina 2018. Characterisation of circulating extracellular vesicles in human obesity. MD Thesis, Cardiff University.
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Abstract

Introduction Extracellular vesicles (EVs) are submicron vesicles released by most cells. They contain protein, enzymes and microRNA of the donor cells and are believed to play a role in paracrine communication. Circulating EVs might reflect heightened inflammatory status in obese individuals and play a role in chronic low grade inflammation associated with obesity. Aims To compare circulating plasma EVs between healthy volunteers across a range of BMI and morbidly obese individuals attending a multidisciplinary weight loss clinic, and to assess the effects of lifestyle changes and bariatric surgery on the circulating EV profile. Finally, to characterise EVs derived from subcutaneous and visceral fat depots. Methods Plasma EVs were isolated by differential centrifugation. EV cellular origin (platelets CD41, monocytes/macrophages CD11b, erythrocytes CD235a, endothelial cells CD144) and adipocytokine expression (IL6, TNFα, interferon γ, adiponectin, FABP4, PPARγ) were evaluated by TRF immunoassay. Results Circulating EV profile and concentration in metabolically healthy volunteers was unaffected by BMI (all p=ns). The EV profile in healthy men was more pro-inflammatory compared to women, with higher EV-expressed CD41, CD144, IL-6, interferon γ and FABP4 (all p<0.05). This was accompanied by lower plasma adiponectin concentration in males (128 μg/mL vs. 272.3μg/mL, p<0.005). Plasma FABP4 correlated strongly with BMI (r=0.91, p<0.005) and was lower in healthy lean versus obese individuals (13.5(6.4) vs 23.8(6.4) ng/mL, respectively (p<0.05)). Dietary and lifestyle management affected the EV profile, with lower signals observed from platelet-derived EVs (p<0.05) as well as FABP4-, TNFα- and Interferon ϒ-expressing EVs at 6 months’ follow-up (p<0.05, p=0.05, p=0.06, respectively). Bariatric surgery led to transient increase in EV and plasma FABP4 at 1 month (p<0.05) which is likely secondary to increased lipolysis during that period. The exosomal marker CD9 correlated with FABP4, interferon γ, adiponectin and TNFα (r=0.49, r=0.41, r=0.59, r=0.53, all p<0.05), suggesting that exosomes are the main carriers of these adipokines. Adipocyte-derived EVs from both visceral and subcutaneous fat depots were found to express numerous adipokines involved in various biological processes and molecular pathways. Conclusion EVs can be regarded as diverse biological vectors playing an important role in regulation of adipose tissue homeostasis and inflammatory processes. Their concentration, cellular origin and content do not directly correlate with BMI but are affected by gender and the presence of obesity-driven comorbidities.

Item Type: Thesis (MD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 27 March 2019
Last Modified: 27 Mar 2019 10:42
URI: http://orca.cf.ac.uk/id/eprint/121113

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