Adipose tissue inflammation in obesity and the influence of marine long chain polyunsaturated omega-3 fatty acids

Obesity is an excess of adipose tissue and is linked with increased inflammation that enhances risk of type-2 diabetes and cardiovascular disease. Despite this knowledge, a comprehensive overview of the inflammatory state of subcutaneous white adipose tissue (scWAT), which is the main pool for excess dietary lipid storage and plays a major role in whole body endocrine processes, is not reported for humans, particularly in those in which metabolic syndrome is yet to manifest. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been widely examined for their anti-inflammatory effects including modulating gene expression and secretion of systemic inflammatory markers. The research described in this thesis explores scWAT fatty acid (FA) and lipid metabolite composition, the whole tissue transcriptome, protein expression, enzyme activity, and tissue morphology in metabolically healthy obese individuals in comparison to normal weight individuals to provide a comprehensive overview of the inflammatory and metabolic state of the tissue in this condition. Furthermore, it explores the anti-inflammatory potential of a 12-week fish oil (FO) intervention on these tissue parameters. Metabolically healthy obesity (MHO) was associated with an altered FA composition and lipid metabolite profile of scWAT. There was a lower proportion of saturated fatty acids, a higher proportion of monounsaturated fatty acids (MUFA), a higher proportion of arachidonic acid (AA) and concentrations of respective oxylipins and COX-2 protein, lower concentrations of DHA oxylipins, and an alteration of the endocannabinoid system (ECS). MHO was further associated with an altered transcriptome suggestive of enhanced inflammation, immune response, tissue remodelling and expansion, altered lipid and carbohydrate metabolism, and lipid mobilization. This was concordant with tissue morphology which showed evidence of adipocyte hypertrophy and the presence of macrophages arranged in crown like structures. Chronic supplementation with EPA+DHA increased concentrations of sWAT omega-3 FAs and derived oxylipins and decreased AA oxylipins, with an effect on the ECS predominantly in normal weight individuals. EPA+DHA modulated the scWAT transcriptome suggesting promotion of tissue remodelling and down regulation of cell differentiation and the chronic inflammatory response, but to a lesser extent in MHO than in normal weight individuals. This lesser effect in MHO may be explained by several processes observed to be altered in MHO at study entry including mobilization and metabolism of EPA and DHA, in addition to greater proportions of omega-6 PUFA which persisted after 12-week FO intervention. The ratio of omega-6:omega-3 FA is of importance and therefore, greater concentrations of EPA and DHA may be required in these individuals to alter this ratio and subsequent oxylipin synthesis and transcriptome modulation. These data suggest MHO is associated with enhanced sWAT inflammation in the context of tissue expansion, remodelling, and alteration to lipid metabolism and signalling. Furthermore, the data suggest that sWAT from metabolically healthy obese individuals without metabolic syndrome maintains some degree of normal function in that it is not fibrotic and is sensitive to dietary lipid manipulation. EPA+DHA modulated synthesis of EPA, DHA and AA derived oxylipins and the transcriptome but resistance to these effects, particularly on the ECS, was exhibited in MHO