1. Cell Biology

LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation

  1. Chan Hee J Choi
  2. William Barr
  3. Samir Zaman
  4. Corey Model
  5. Annsea Park
  6. Mascha Koenen
  7. Zeran Lin
  8. Sarah K Szwed
  9. François Marchildon
  10. Audrey Crane
  11. Thomas S Carroll
  12. Henrik Molina
  13. Paul Cohen  Is a corresponding author
  1. Rockefeller University, United States
  2. Yale University, United States
https://doi.org/10.7554/eLife.81559
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Cite this article
  1. Chan Hee J Choi
  2. William Barr
  3. Samir Zaman
  4. Corey Model
  5. Annsea Park
  6. Mascha Koenen
  7. Zeran Lin
  8. Sarah K Szwed
  9. François Marchildon
  10. Audrey Crane
  11. Thomas S Carroll
  12. Henrik Molina
  13. Paul Cohen
(2022)
LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation
eLife 11:e81559.
https://doi.org/10.7554/eLife.81559
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Abstract

While dysregulation of adipocyte endocrine function plays a central role in obesity and its complications, the vast majority of adipokines remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white and interscapular brown adipocytes. Over 600 proteins were identified, the majority of which showed cell type-specific enrichment. We here describe a metabolic role for leucine-rich α-2 glycoprotein 1 (LRG1) as an obesity-regulated adipokine secreted by mature adipocytes. LRG1 overexpression significantly improved glucose homeostasis in diet-induced and genetically obese mice. This was associated with markedly reduced white adipose tissue macrophage accumulation and systemic inflammation. Mechanistically, we found LRG1 binds cytochrome c in circulation to dampen its pro-inflammatory effect. These data support a new role for LRG1 as an insulin sensitizer with therapeutic potential given its immunomodulatory function at the nexus of obesity, inflammation, and associated pathology.

Data availability

Proteomic dataset has been deposited to Proteomexchange PRIDE under accession PXD035318. RNA-Seq data have been deposited to GEO under accession GSE208219. All original gels and blots are available as Source Data Files.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Chan Hee J Choi

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. William Barr

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Samir Zaman

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Corey Model

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Annsea Park

    Department of Immunobiology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Mascha Koenen

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1024-4506

  7. Zeran Lin

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4418-2443

  8. Sarah K Szwed

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. François Marchildon

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Audrey Crane

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Thomas S Carroll

    Bioinformatics Resouce Center, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Henrik Molina

    Proteomics Resource Center, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8950-4990

  13. Paul Cohen

    Laboratory of Molecular Metabolism, Rockefeller University, New York, United States
    For correspondence
    pcohen@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2786-8585

Funding

American Diabetes Association (1-17-ACE-17)

  • Paul Cohen

National Institutes of Health (RC2 DK129961)

  • Paul Cohen

National Institute of General Medical Sciences (T32GM007739)

  • Chan Hee J Choi
  • Sarah K Szwed

Sarnoff Cardiovascular Research Foundation

  • Samir Zaman

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 studies were performed in accordance with the institutional guidelines of the Rockefeller University Institutional Animal Care and Use Committee (IACUC) protocol (18016-H). Experiments involving adenoviral and AAV8 vectors were performed under general anesthesia using isoflurane, in accordance with the institutional ABSL-2 guidelines.

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Preprint posted: July 12, 2021 (view preprint)
  2. Received: July 2, 2022
  3. Accepted: November 6, 2022
  4. Accepted Manuscript published: November 8, 2022 (version 1)
  5. Version of Record published: November 18, 2022 (version 2)

Copyright

© 2022, Choi 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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  1. Chan Hee J Choi
  2. William Barr
  3. Samir Zaman
  4. Corey Model
  5. Annsea Park
  6. Mascha Koenen
  7. Zeran Lin
  8. Sarah K Szwed
  9. François Marchildon
  10. Audrey Crane
  11. Thomas S Carroll
  12. Henrik Molina
  13. Paul Cohen
(2022)
LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation
eLife 11:e81559.
https://doi.org/10.7554/eLife.81559

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