Metabolic Actions of Omega-3 Fatty Acids on Inflammation


Principal Investigator: Michael Miller
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2012-07-01 - 2014-05-31
more information: NIH RePORT

Detail Information

Research Grants31

  1. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
    Victor J Hruby; Fiscal Year: 2013
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  4. The Metabolic Impact of Congenital Heterozygous ApoC-III Deficiency in Humans
    TONI ILANA POLLIN; Fiscal Year: 2013
    ..This project will look more closely at the effects of the deficiency on human metabolism to better understand the function of the apoC-III protein and its potential as a drug target. ..
  5. Lifespan Extension Despite Greatly Elevated Insulin and Body Fat
    David E Harrison; Fiscal Year: 2013
    ..Effects of DR that extend life spans in both normal control and ob/ob mice in this study are likely targets for interventions to retard aging and extend healthy lifespan in human beings. ..
  6. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  7. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
  8. JHU-UMD Diabetes Research Center
    Fredric E Wondisford; Fiscal Year: 2013
    ..The Enrichment Program will facilitate the interaction within and between Johns Hopkins University and the University of Maryland. ..
  9. Alterations in Adipocyte Lipid Metabolism by Trans-10, Cis-12 CLA Supplementation
    LAURA JANE DEN HARTIGH; Fiscal Year: 2013
    Houchun H Hu; Fiscal Year: 2013
    ..This project will contribute novel and non-invasive magnetic resonance imaging techniques to accurately and reliably study fat across the entire human body. ..
  11. Metabolic Markers and Predictors of Childhood Obesity
    Sonia Caprio; Fiscal Year: 2013
    ..abstract_text> ..
  12. Function of the Myo-adipo Axis in Human Obesity and Type 2 Diabetes
    ROBERT ROY HENRY; Fiscal Year: 2013
    ..Results from this project will provide molecular mechanisms for metabolic dysfunction seen in vivo in obesity and T2D and identify possible targets for therapeutic interventions. ..
    IRA JAY GOLDBERG; Fiscal Year: 2013
    ..The experiments will use novel genetically modified mice, cultured myocytes, and state of the art lipidomics. ..
  14. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
    ..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
  15. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..