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Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity

  1. Kasparas Petkevicius  Is a corresponding author
  2. Sam Virtue
  3. Guillaume Bidault
  4. Benjamin Jenkins
  5. Cankut Çubuk
  6. Cecilia Morgantini
  7. Myriam Aouadi
  8. Joaquin Dopazo
  9. Mireille Serlie
  10. Albert Koulman
  11. Antonio Vidal-Puig  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. Fundacion Progreso y Salud, Spain
  3. Karolinska Institute, Sweden
  4. Amsterdam University Medical Center, Netherlands
Research Article
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Cite this article as: eLife 2019;8:e47990 doi: 10.7554/eLife.47990

Abstract

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTa), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTa-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTa-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs.

Article and author information

Author details

  1. Kasparas Petkevicius

    Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    kp416@medschl.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Sam Virtue

    Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Guillaume Bidault

    Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Benjamin Jenkins

    Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Cankut Çubuk

    Clinical Bioinformatics Area, Fundacion Progreso y Salud, Sevilla, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4646-0849
  6. Cecilia Morgantini

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3142-2508
  7. Myriam Aouadi

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6256-7107
  8. Joaquin Dopazo

    Clinical Bioinformatics Area, Fundacion Progreso y Salud, Sevilla, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Mireille Serlie

    Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Albert Koulman

    Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Antonio Vidal-Puig

    Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    ajv22@medschl.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4220-9577

Funding

Wellcome (4-year PhD programme in Metabolic and Cardiovascular Disease)

  • Kasparas Petkevicius

British Heart Foundation (Programme Grant RG/18/7/33636)

  • Kasparas Petkevicius
  • Sam Virtue
  • Guillaume Bidault
  • Antonio Vidal-Puig

Wellcome (Strategic Award)

  • Kasparas Petkevicius
  • Sam Virtue
  • Guillaume Bidault
  • Antonio Vidal-Puig

Medical Research Council (MRC_MC_UU_12012/5)

  • Kasparas Petkevicius
  • Sam Virtue
  • Guillaume Bidault
  • Antonio Vidal-Puig

Medical Research Council (MRC_MC_UU_12012/2)

  • Kasparas Petkevicius
  • Sam Virtue
  • Guillaume Bidault
  • Antonio Vidal-Puig

Spanish Ministry of economy and competitiveness (SAF2017-88908-R)

  • Cankut Çubuk
  • Joaquin Dopazo

Swedish Research council (2015-03582)

  • Cecilia Morgantini
  • Myriam Aouadi

Strategic research program in Diabetes at Karolinska Institutet (M.A.)

  • Cecilia Morgantini
  • Myriam Aouadi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal protocols were conducted in accordance with the UK Home Office and Cambridge University ethical guidelines.

Human subjects: Human samples used for this work had been generated as part of another study, that has already been published and is referenced in our manuscript (de Weijer et al, 2013). This study had been conducted to the highest ethical standards, and the ethics statement is available in the published paper.

Reviewing Editor

  1. Michael Czech, University of Massachusetts Medical School, United States

Publication history

  1. Received: April 26, 2019
  2. Accepted: August 15, 2019
  3. Accepted Manuscript published: August 16, 2019 (version 1)

Copyright

© 2019, Petkevicius et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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