Long chain ω-3PUFA fatty acid supplementation in animal models of diet-induced-obesity has consistently shown to improve insulin sensitivity. The same is not always reported in studies with obese, insulin resistant (IR) subjects. We studied whether high-dose ω-3PUFA supplementation for 3 months improves insulin sensitivity and adipose tissue (AT) inflammation in severely obese, IR subjects. Thirteen obese, IR subjects underwent 80 mU/m 2· min euglycemic-hyperinsulinemic clamp with subcutaneous (Sc) AT biopsy before and after three months of ω-3PUFA (DHA & EPA, 4g/daily) supplementation. Cytoadipokine plasma profiles were assessed before and after ω-3PUFA. AT-specific inflammatory gene expression was evaluated on Sc fat biopsies. Microarray analysis was performed on the fat biopsies collected during the program. Palmitic and stearic acid plasma levels were significantly reduced (P<0.05) after ω-3PUFA. Gene expression of pro-inflammatory markers and adipokines were improved after ω-3PUFA (P<0.05). Systemic inflammation was decreased after ω-3PUFA, as shown by cytokine assessment (P<0.05). These changes were associated with a 25% increase in insulin-stimulated glucose disposal (4.67±0.62mg/kg ffm•min vs 5.87±0.79mg/kg ffm•min) despite no change in
body weight. Microarray analysis identified 53 probe sets significantly altered post- ω-3PUFA, with APOE being one of the most upregulated genes. High dose of long chain ω-3PUFA supplementation modulates significant changes in plasma fatty acid profile, AT and systemic inflammation. These findings associate with significant improvement of insulin-stimulated glucose disposal. Unbiased microarray analysis of Sc fat biopsy identified APOE as the most differentially regulated gene after ω-3PUFA 22 supplementation. We speculate that ω-3PUFA increases macrophage-derived APOE mRNA levels with anti-inflammatory properties.