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Adipose tissue (AT) distribution has significant impact on disease, with central abdominal fat increasing the risk of T2DM and CVD compared with gluteo-femoral (thigh) fat, however limited studies to date have addressed the site-specific nature of human epicardial AT in relation to thigh fat. Our previous studies have implicated epicardial AT as a source of inflammatory cytokines which may influence myocardial function, due to its location. This study examined, in matched paired epicardial and thigh AT from patients undergoing coronary artery bypass grafting (CABG), the intrinsic nature of epicardial and thigh AT during inflammation, mediators of the innate immune pathway toll like receptors (TLR) 2 & 4, NFκB & JNK as potential key mediators of adipocytokine production, CD68 gene expression (macrophage marker, to investigate the role of macrophages in epicardial AT) and whether elevated systemic endotoxin levels may initiate the innate immune response. Fasted serum was taken from CABG subjects (Age:63.8±8.4yrs, BMI:27.8±3.5kg/m², n=72) and non-CAD subjects (Age:61.8±8.0yrs, BMI:27.9±3.3kg/m², n=60). A sub-cohort of paired epicardial and gluteo-femoral AT was obtained from CABG subjects (Age:66.7±6.7yrs, BMI:28.4±3.6 kg/m⊃2, n=16). Endotoxin was measured by LAL assay. In epicardial AT, gene expression data showed associations between CD68 with TLR2 (r=0.94, p<0.001), TLR4 (r=0.95, p<0.001) and TNFα (r=0.81, p<0.001). NFκB and the IKK protein expression was higher in epicardial AT compared with thigh (NF κB p=0.06, IKKβ p=0.01, IKKγp=0.001) as well as JNK expression (p<0.01). Lastly, serum endotoxin was raised in CABG patients compared with controls (p<0.05). In brief epicardial AT showed increased NF κB, IKKβ and JNK levels compared with matched thigh AT; suggesting a depot-specific inflammatory response. Thus enhanced activation of the NF κB and JNK pathways in the epicardial depot may arise through increased simultaneous activation of macrophages and adipocytes. Also such an inflammatory response in AT may arise due to gut-derived endotoxin levels which were increased in CABG patients. In conclusion, these studies show epicardial AT as a source of inflammatory cytokines through NFκB and other key inflammatory pathways highlighting the significance of macrophages in epicardial AT. [ABSTRACT FROM AUTHOR]

Central obesity is strongly associated with sub-clinical inflammation, insulin resistance (IR) and type 2 diabetes mellitus (T2DM), but the intracellular mechanisms involved in the pathogenesis of central obesity remain unclear. Recent studies have implicated NF κB and c-Jun N terminal kinase (JNK) as central molecules linking insulin action and inflammation in mice. Our study aimed to investigate (1) the central inflammatory intracellular signaling pathways involving NF κB and JNK activation in abdominal subcutaneous (AbdSc) and omental (Ore) human adipose tissue, (2) the influence of adiposity and diabetic status on the activation of the NF κB and its key intermediates and JNK within these AT depots and (3) the effects of TNFα, a known mediator of inflammation in mice, on NF κB and JNK activity in human AbdSc adipocytes. Our data showed that ex vivo IKKβ, IKKγ, I κBα and I κB α -P protein expression was increased in Om AT compared with AbdSc AT (p<0.01). The ratio of active NF κB to total NF κB expression (NF κB ratio) was upregulated in Om AT compared with AbdSc in both lean and obese subjects (p<0.05). Whilst, phosphospecific JNK1 was increased 5.8 fold in the AbdSc depot, (p<0.01), compared with Om AT. In in vitro TNF α treated AbdSc adipocytes NF κB activity increased over time (2-48 hr, p<0.05), however JNK activity remained unchanged. In conclusion, these findings suggest distinct inflammatory signaling pathways with increased NF κB in human Om AT and JNK in AbdSc AT. In addition, NF κB was influenced by obesity and diabetic status, whilst TNF α treated AbdSc lead to activation of NF κB and not JNK. Consequently, NF κB appears to play a more central role in inflammatory mediated metabolic disease than JNK, highlighting NF κB as a potential key target for therapeutic intervention. [ABSTRACT FROM AUTHOR]