Clinical studies suggest that the marine-derived omega-3 polyunsaturated fatty acids (PUFAs), eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) improve high triglyceride (TG) and blood pressure (BP) constituents of the metabolic syndrome (MetS) , and also reduce cytokines; however, we are not aware of any studies that have examined the mechanisms underlying these effects in overweight men and women with MetS. Of the few human studies evaluating EPA/DHA supplementation on lipid metabolism, most were conducted for short periods in normal weight or non-hyperTG subjects and did not measure effects on adipocyte lipolysis, adipokine secretion, lipogenesis or visceral fat. We hypothesize that EPA/DHA supplementation will not only reduce plasma TG, but also decrease systemic and tissue inflammation, insulin resistance (HOMA-IR), adipose tissue lipolysis and cytokine release to enhance the TG storage capacity of adipose tissue. The reduction in inflammation and increase in insulin sensitivity will remodel adipose tissue to function more efficiently in TG uptake and storage, thus reducing circulating FFAs and cytokines. We further postulate that these metabolic effects may decrease ectopic fat deposition in viscera (intra-abdominal fat and muscle), an intriguing, novel outcome that provides rationale for the 9-month treatment plan. The Aims of this R21 proposal are to conduct a pilot, 9 month randomized trial in adults with MetS comparing the effects of EPA/DHA vs. ALA supplementation on 1) Metabolic (e.g., lipoproteins, inflammatory cytokines, acute phase reactants, glucose tolerance/insulin resistance) and adipose tissue metabolism (basal and insulin suppressed lipolysis (ED50), cytokine release and lipogenesis), and 2) Regional fat distribution quantified as, visceral and subcutaneous adipose volumes and muscle lipid accumulation by CT-scan and body composition (total and regional fat mass) by dual energy absorptiometry (DXA). This proposal capitalizes on collaboration among experienced investigators in lipoprotein metabolism, nutritional biochemistry and adipocyte biology in a NIDDK-Nutrition Obesity Research Center to examine a clinical/therapeutic question using a novel study design and methodologies that will determine the mechanisms by which omega-3 PUFA (EPA, DHA and ALA) supplementation affect adipocyte biology to reduce inflammation, lipolysis, TG and ectopic fat accumulation in adults with MetS. Favorable outcomes could translate into therapeutic trials to test the efficacy of EPA/DHA supplements, either singly or in combination with other drugs to reduce TG, systemic inflammation, insulin resistance and CVD risk. PUBLIC HEALTH RELEVANCE: The metabolic syndrome raises the risk of heart disease and is currently at epidemic proportions in the U.S. It consists of 3 of the following components: central obesity, high triglycerides, low HDL, abnormal blood pressure and impaired fasting glucose levels. Previous studies have suggested that omega-3 fish oil may influence some of these components but the mechanisms involved are not well understood. Therefore, this proposal will investigate how omega-3 fish oils affect inflammation, lipids and fat breakdown by comparing it to a non-fish oil omega-3 supplement (linolenic acid). Favorable outcomes from this study could translate into a new approach to improve heart disease risk in men and women with the metabolic syndrome.