Metabolic Actions of Omega-3 Fatty Acids

Metabolic Actions of Omega-3 Fatty Acids on Inflammation and Adipocyte Lipolysis in the Metabolic Syndrome

National Institutes of Health (NIH), US Department of Veterans Affairs, National Heart, Lung, and Blood Institute (NHLBI)

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 placebo. Favorable outcomes from this study could translate into a new approach to improve heart disease risk in men and women with the metabolic syndrome.

Metabolic Actions of Omega-3 Fatty Acids on Inflammation and Adipocyte Lipolysis in the Metabolic Syndrome Epidemiological studies identify metabolic syndrome (MetS) as a biomarker of cardiovascular disease (CVD) risk, and recent AHA scientific statements recommend intensive lifestyle diet and exercise measures to reduce risk. Marine-derived omega-3 polyunsaturated fatty acids such as, eicosapentanoic acid (EPA) improve many constituents of the metabolic syndrome such as lowering fasting TG and glucose levels, inflammation, insulin resistance and blood pressure. These improvements may be mediated by increased fat cell storage and metabolism and lipids, reducing inflammation and ectopic fat deposition in visceral abdominal tissue, muscle and liver that results in excessive pro-inflammatory intra-abdominal fat (IAF), insulin resistance and reduced levels of HDL cholesterol, hallmark characteristics of the MetS. The anti-inflammatory actions of EPA lower acute phase reactants (APRs) and proinflammatory mediators are mechanisms for their lipid lowering and insulin sensitizing effects to reduce CVD risk. The systematic investigation of marine-derived omega-3 PUFAs on these inflammatory, metabolic and physiological parameters will provide new mechanistic insights for the therapeutic use of a potentially beneficial, safe nutraceutical, EPA in patients with MetS. Thus, it is our hypothesis that supplementation of marine-derived omega-3 PUFAs, will reduce constituents of MetS as well as systemic and tissue inflammation, insulin resistance (HOMA-IR), adipocyte lipolysis and cytokine release from AT to enhance TG storage capacity of subcutaneous AT. 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 postulate that these metabolic effects may decrease ectopic fat deposition in viscera (IAF and muscle), an intriguing, novel outcome that provides rationale for the 9 month treatment. The Specific Aims are to conduct a pilot 9 month randomized trial in adults with high Tg and at least one other component of the MetS to compare the effects of EPA vs. placebo on: Aim 1: Metabolic (e.g., lipoproteins, inflammatory cytokines, acute phase reactants, glucose tolerance/insulin resistance) and adipose tissue responses (basal and insulin suppression of lipolysis (ED50), LPL activity, cytokine release and lipogenesis). Aim 2: Regional fat distribution quantified anthropometrically as waist and hip circumference, 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). These outcomes have potentially intriguing therapeutic implications for marine derived omega-3 PUFA supplementation as part of a lifestyle program for patients at increased cardiometabolic risk.

Biochemical measurements of lipids, glucose homeostasis, inflammatory markers, and adipocyte responses to mediators of lipolysis

Metabolic (e.g., lipoproteins, inflammatory cytokines, acute phase reactants, glucose tolerance/insulin resistance) and adipose tissue responses (basal and insulin suppression of lipolysis (ED50), LPL activity, cytokine release and lipogenesis).

Determination of regional fat distribution, visceral and subcutaneous adipose volume and body composition

Regional fat distribution quantified anthropometrically as waist and hip circumference, 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).

Inclusion Criteria: Metabolic Syndrome, including 2 of the following: Treated Hyperlipidemia or Untreated Triglycerides > 150 mg/dL Waist circumference (inches) > 35 (women) or >40 (men) And at least 1 additional factor: Treated Hypertension or Untreated Blood pressure >130/85 and < 160/100 mm Hg HDL-C < 40 mg/dL men < 50 mg/dL women Glucose > 100mg/dL and HbA1c < 6.1% Exclusion Criteria: Fasting TG > 500 mg/dL or LDL > 180 mg/dL Fasting glucose> 125 mg/dL or history of diabetes mellitus Hematologic or malignant disorders Morbid Obesity (BMI > 50 kg/m2) Endocrine (thyroid) or metabolic disorders (unless treated and under control) Alcohol consumption greater than (2) 4-ounce glasses of table wine, (2) 12-oz bottles of beer or 2 shots of spirits in men or women Active IV drug abuse within the past 6 months Clinical depression (per PI evaluation) Immunosuppressive or other therapy that would interfere with research testing