Background Long 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. Objective We studied whether high-dose ω-3PUFA supplementation for 3 months improves insulin sensitivity and adipose tissue (AT) inflammation in IR subjects with obesity. Methods Thirteen 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. Results 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 (4.7 ± 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. Conclusion High 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.
Eosinophils (EOS) have been shown to play a major role in animal adipose tissue (AT) metabolism by promoting insulin sensitivity (IS) through an increase in alternatively activated macrophages (M2). Additionally, AT EOS are known to be decreased in obese mice. Currently, translational evidence is lacking for the role of EOS in human AT metabolism and IS. We investigated whether human AT-resident EOS numbers, as in animal models, are decreased in obese subjects and correlate with their degree of insulin resistance (IR). To date, we have studied 16 lean subjects (F15/M1, age 43 +2 years old; BMI 22.5+0.4kg/m2; HOMA-IR: 0.99 +0.38) and 22 obese, IR subjects (17F/5M, age 42 +1.3 years old; BMI: 38.9 +1.0kg/m2; HOMA-IR:5.0 +1.6) undergoing elective laparoscopic surgery. During surgical procedure, subcutaneous (SC) and omental (OM) fat was harvested. Stromal vascular fraction (SVF) was isolated after collagenase digestion of the fat samples. SVF was subjected to FACS analysis using BD Biosciences FACSAria III Cell Sorter with EOS count normalized as percent of CD45+ cells. Viable EOS were isolated and cytospin preparation was stained with a Diff-Quik. EOS isolated from SC AT of lean(L) subjects were found to significantly outnumber those obtained from obese (Ob) subjects by a 2.1:1 ratio (SC L:2.34 +0.29 vs. SC Ob: 1.11 +0.21, P<0.03). A similar, but non-significant, trend was observed in OM. Furthermore, the number of SC AT-EOS was significantly inversely correlated with BMI, % fat and QUICKI index. qPCR analysis of SC AT mRNA revealed significantly increased classically activated macrophage markers (M1) (IL-1, IL-6, TNFα) in Ob vs. L, respectively while M2 markers (ARG-1, CCL24, CCL26) were significantly decreased in Ob vs. L. Based on these results we propose that, as in animal models, AT-resident EOS mediate AT metabolism and potentially IS by preserving an anti-inflammatory milieu within lean AT. Further studies are needed to elucidate the mechanism(s) involved. Disclosure J.D. Hernandez: None. T. Li: None. C. Rau: None. M.Y. Masuda: None. J.A. Madura: None. E.A. Jacobsen: None. E. DeFilippis: None. Funding Arizona Department of Health Services (14-00003606); Arizona Biomedical Research Commission; Kathryn H. and Roger Penske Career Development Award
Inflammation of adipose tissue (AT) is key for the development of insulin resistance (IR) in obesity. We previously showed that 3 months supplementation of fish oil (FO, 4g/day), a well-known anti-inflammatory agent, induced 25% improvement in glucose disposal during euglycemic-hyperinsulinemic clamp in 13 obese, insulin resistant subjects (ADA abstract Hernandez J., et al 2017). To explore the mechanism(s) linked to this improvement, we first performed a microarray analysis of subcutaneous (SC) AT samples pre and post FO supplementation. Functional analysis indicated anti-inflammatory pathways as the principal pathways to be enriched after FO supplementation. We identified APOE (1.87 Fold Change (FC) Post vs. Pre-FO, P=0.004) among the most significantly enhanced genes, as APOE was common to the top 5 enriched anti-inflammatory pathways. RT-PCR analysis confirmed the changes in expression levels of several genes in these pathways including APOE, APOC1, MS4A6E, MMP9, MMP7, DEFB132, C1QTNF7, and POPDC3, thereby validating the microarray findings. Plasma and SC AT RT-PCR analysis showed significantly decreased inflammatory markers (IL1B: -0.28 FC, P=0.04, MCP1: -0.44 FC, P=0.04, CD68: -0.36 FC P=0.01) post vs. pre-FO. Additionally, mRNA adiponectin levels increased (FC +0.45 Post vs. Pre, P=0.02), while leptin decreased (FC -.030 Post vs. Pre, P=0.02). Furthermore, ω3PUFA supplementation significantly reduced plasma FFA levels (Post-FO: 0.578+0.061mM vs. Pre-FO: 0.719 +0.055mM P<0.05). Taken together, our data suggests that ω3PUFA supplementation-induced improvement of insulin sensitivity in obese, insulin resistant subjects is attributed to the reduction of plasma FFA levels. This then associates with inhibition of inflammatory processes mediated by APOE. Additional studies are needed to further analyze the mechanism(s) linking FO to AT APOE gene expression, inflammation and insulin sensitivity. Disclosure C. Rau: None. T. Li: None. J.D. Hernandez: None. M.Y. Masuda: None. X. Zhang: None. P. Wang: None. D.K. Coletta: None. E. DeFilippis: None. Funding Arizona Department of Health Services (14-00003606); Kathryn H. and Roger Penske Career Development Award
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