The effect of apolipoprotein E (APOE) genotype and long chain omega 3 fatty acids on body weight and inflammation
Obesity-associated adipose tissue (AT) inflammation is characterised by macrophage (ATM) infiltration and polarisation from anti-inflammatory (M2) towards pro-inflammatory (M1) phenotype. Long chain (LC) n-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert various beneficial effects on inflammatory and metabolic parameters in relation to obesity. The apolipoprotein Epsilon 4 (APOE4) genotype is associated with a pro-inflammatory state, lower adiposity yet greater metabolic dysfunction in obesity and an altered LC n-3 PUFA status compared to APOE3 genotype. This PhD project aimed to investigate the relationships between APOE genotype, adiposity, LC n-3 PUFA status and inflammation. In an existing data set of 312 participants involved in a fish oil intervention trial [Caslake et al., 2008, Kofler et al., 2012] we demonstrated that age, BMI and habitual oily fish intake, but not APOE Epsilon genotype, determined plasma LC n-3 PUFA status. APOE Epsilon genotype interacted with -219G/T polymorphism (rs405509) to determine plasma apoE and select inflammatory marker concentrations. In human APOE targeted replacement (TR) mice fed a high-fat diet (HFD) without or with 30 g EPA+DHA / kg of diet (HFD+FO) for 8 weeks, APOE3, but not APOE4, mice develop obesity and impaired glucose tolerance upon HFD feeding that is prevented by dietary fish oil. ATM infiltration and phenotype was similar between APOE3 and APOE4 mice. Fish oil increased the number of ATM without influencing their phenotype. LC n-3 PUFA enrichment of AT was similar, although EPA and DHA levels tended to be 10 – 20% lower in APOE4 mice compared to APOE3 mice on HFD+FO. In primary murine bone marrow-derived macrophages the APOE4 genotype was associated with higher prevalence of the anti-inflammatory M2 phenotype compared to APOE3 genotype. In conclusion, our findings contribute to the current understanding of the potential mechanisms through which the APOE Epsilon genotype modulates adiposity and its metabolic impact.
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