Omega-3 PUFA suppress adipochemokines in human obesity

Summary

Principal Investigator: Rachana Shah
Abstract: DESCRIPTION (provided by applicant): Obesity and its resultant complications represent a major public health;further understanding of the underlying pathophysiology will aid the development of preventive and therapeutic modalities. As a pediatric endocrinologist, the P.I. Dr Shah has a committed interest in studying the early mechanistic processes involved in obesity-related metabolic dysregulation, with the hope of exploring novel preventive and treatment options. Her ultimate career goal is to become an independent translational researcher in the field of endocrinology, with a focus in obesity and adipose tissue biology across the pediatric and adult age spectrum. Through her current work with her mentor and training in the Masters in Translational Research program, she has developed essential skills and experience in clinical and translational research. This will allow her to perform the work proposed in this application, which integrates a human clinical trial with studies in human tissues and cells to explore novel pathways in obesity-related adipose inflammation. To acquire further expertise and knowledge as she transitions to independence, Dr Shah has devised a comprehensive career development plan that takes full advantage of the rich research, educational, and collaborative environment at the Children's Hospital of Philadelphia and the University of Pennsylvania. Dr Shah's career plan includes strong mentorship in translational research, didactic coursework in genetics, immunology, and bioinformatics, focused training in necessary laboratory skills and aspects of clinical research, scientific enrichment and professional development through attendance of intra- and extra-mural, seminars and conferences, and clearly delineated steps to independence. She has the full support of the Department of Pediatrics and Division of Endocrinology to ensure adequate time and resources for this training. Additionally, she will receive guidance through her mentors, Dr Muredach Reilly and Dr Karen Teff, and a carefully selected advisory committee of experts in critical areas of her proposed research. In order to complete her proposed studies, Dr Shah will have access to resources in the Penn/CHOP CTSA-sponsored Clinical and Translational Research Center (CTRC), Dr Reilly's laboratory, core facilities, and statistical expertise. Through the completion of the research and educational plans outlined in this application, Dr Shah will gain the experience necessary to establish an independent translational research program exploring mechanisms in obesity across the adult-pediatric spectrum. Murine long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) are used clinically to treat dyslipidemia and are demonstrated in pre-clinical cell and rodent models to decrease adipocyte and monocyte inflammation and prevent adipose leukocyte infiltration during high-fat feeding;in vivo human data, however, is lacking. A key driver of adipose inflammation and macrophage infiltration is adipochemokine signaling, including the CCL2-CCR2 and CX3CL1-CX3CR1 pathways. Whether LC n-3 PUFA anti-inflammatory actions in adipose are mediated via these chemokine systems is suggested by decreased CCL2 levels in mice fed n-3 PUFA but has not specifically been explored, The mechanisms by which LC n-3 PUFA exerts anti-inflammatory effects in adipose are also not clearly defined. Recently a LC n-3 PUFA receptor, GPR120, has been identified that in mouse and cell models appears to modulate n-3 PUFA inhibition of nuclear factor kappa beta (NF signaling to decrease inflammation in cells and adipose tissue. In humans, loss of function of GPR120 confers increased risk of obesity. Together these findings suggest a potential mechanism by which LC n-3 PUFA attenuates obesity- related adipose inflammation. We hypothesize that LC n-3 PUFA modulate adipocyte-macrophage chemokine signaling (CCL2-CCR2 and CX3CL1-CX3CR1) to decrease systemic and adipose inflammation via GPR120 inhibition of NF- B signaling. This application addresses the following hypotheses: 1) LC n-3 PUFA treatment of primary human adipocytes in vitro suppresses chemokine-induced adipocyte inflammation and adipocyte-monocyte interactions via GPR120 2) LC n-3 PUFA treatment of human monocytes and macrophages in vitro modifies CX3CL1-CX3CR1 and CCL2-CCR2 to reduce the inflammatory state of these leukocytes and resultant interactions with adipocytes in a GPR120-dependent manner and 3) treatment of obese human subjects with the n-3 PUFA supplement Lovaza, compared to placebo, regulates the CX3CL1-CX3CR1 and CCL2-CCR2 chemokine systems to reduce inflammatory leukocyte recruitment into human adipose. In vitro studies in primary human cells will assess effects of individual n-3 PUFAs and GPR120 agonists on baseline and inflammatory stimulated chemokine signaling, CX3CL1-CX3CR1 and CCL2-CCR2 induced monocyte-adipocyte adhesion and migration, and.NF activation. Knockdown of GPR120 and NFkB will be used to determine whether anti- inflammatory effects are modulated by these pathways. For the clinical trial, obese, non-diabetic subjects will be treated for 8 weeks with Lovaza or placebo;visits are planned at baseline and 8 weeks for assessment of insulin sensitivity, adipose and blood chemokine levels, NF signaling factors, and adipose and circulating CX3CR1- and CCR2-expressing macrophage and monocyte quantification via flow cytometry.
Funding Period: 2013-09-01 - 2016-07-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    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. ..
  2. 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. ..
  3. The Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention
    Floyd H Chilton; Fiscal Year: 2013
    ....
  4. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  5. Mayo Clinic SPORE in Ovarian Cancer
    Scott H Kaufmann; Fiscal Year: 2013
    ..The Mayo Clinic SPORE in Ovarian Cancer has the full support of the Mayo Clinic Cancer Center and Mayo Foundation. ..
  6. Cellular Decisions of Differentiation in the GI Tract
    Juanita L Merchant; Fiscal Year: 2013
    ....
  7. Center for Excellence in Diabetes and Obesity Research
    ARUNI BHATNAGAR BHATNAGAR; Fiscal Year: 2013
    ..Continued support to the Center will strengthen the infrastructure of biomedical research at the University of Louisville and will positively impact the field of diabete and obesity research worldwide. ..
  8. Center of Research on Obesity and Cardiovascular Diseases
    Lisa A Cassis; Fiscal Year: 2013
    ....
  9. Mentoring Research Excellence in Aging and Regenerative Medicine
    S Michal Jazwinski; Fiscal Year: 2013
    ..This COBRE will represent the centerpiece of the Tulane Center for Aging, and it will contribute strongly to our building of an exceptional biomedical aging research enterprise in Louisiana. ..
  10. Novel Methods to Assess the Effects of Chemicals on Child Development
    Susan L Schantz; Fiscal Year: 2013
    ..This Center's research will fill an important gap in our knowledge by investigating the effects of these chemicals, both alone and combination with a high fat diet on reproductive and neural development. ..
  11. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  12. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  13. Coordinating Center of Excellence in Social Promotion of Health Equity Research
    GLORIA S MCCUTCHEON; Fiscal Year: 2013
    ..abstract_text> ..
  14. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  15. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  16. Translational Research in Cystic Fibrosis
    Mitchell L Drumm; Fiscal Year: 2013
    ..This goal is also a function of the Biomedical Research Cores. ..
  17. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  18. 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. ..
  19. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
    ..abstract_text> ..