Metabolic Actions of Omega-3 Fatty Acids

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