Abstract
BackgroundLong chain omega-3 polyunsaturated fatty acids (ω-3PUFA) supplementation in animal models of diet-induced obesity has consistently shown to improve insulin sensitivity. The same is not always reported in human studies with insulin resistant (IR) subjects with obesity.ObjectiveWe studied whether high-dose ω-3PUFA supplementation for 3 months improves insulin sensitivity and adipose tissue (AT) inflammation in IR subjects with obesity.MethodsThirteen subjects (BMI = 39.3 ± 1.6 kg/m2) underwent 80 mU/m2·min euglycemic-hyperinsulinemic clamp with subcutaneous (Sc) AT biopsy before and after 3 months of ω-3PUFA (DHA and EPA, 4 g/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.ResultsPalmitic 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 (4.7 ± 0.6 mg/kg ffm•min vs. 5.9 ± 0.9 mg/kg ffm•min) despite no change in body weight. Microarray analysis identified 53 probe sets significantly altered post- ω-3PUFA, with Apolipoprotein E (APOE) being one of the most upregulated genes.ConclusionHigh dose of long chain ω-3PUFA supplementation modulates significant changes in plasma fatty acid profile, AT, and systemic inflammation. These findings are associated with significant improvement of insulin-stimulated glucose disposal. Unbiased microarray analysis of Sc fat biopsy identified APOE as among the most differentially regulated gene after ω-3PUFA supplementation. We speculate that ω-3PUFA increases macrophage-derived APOE mRNA levels with anti-inflammatory properties.
Highlights
adipose tissue (AT) mobilizes its stores as free fatty acids (FFA) which is released during fasting states as fuel for lean tissues [8]
No significant changes in Body mass index (BMI), or fat percentage were identified after 3 months of ω-3PUFA supplementation in the studied subjects (Table 1)
We demonstrated that plasma levels of proinflammatory cytokines MCP-1, TNF-α, IL-1B, INFγ, and GM-CSF were all significantly decreased after 3 months of FO (Fig. 1)
Summary
Obesity is a worldwide public health issue [1], which causes a chronic, low-grade inflammatory state [2, 3]. It predisposes to the development of cardiovascular disease [4], Scottsdale, AZ, USA 4 Department of Biostatistics, Mayo Clinic Arizona, Scottsdale, AZ, USA 5 Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA 6 Division of General Surgery, Mayo Clinic Arizona, Phoenix, AZ, USA insulin resistance [5] and type 2 diabetes mellitus [6], all maladies with high morbidity and mortality rates [7]. The same is not always reported in human studies with insulin resistant (IR) subjects with obesity
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