Metabolic Actions of Omega-3 Fatty Acids
Metabolic Actions of Omega-3 Fatty Acids
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.
Inclusion Criteria:

 -  Metabolic Syndrome, including 2 of the following:

 1. Treated Hyperlipidemia or Untreated Triglycerides > 150 mg/dL

 2. 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