Abstract

During obesity and high fat-diet (HFD) feeding in mice, sustained low-grade inflammation includes not only increased pro-inflammatory macrophages in the expanding adipose tissue, but also bone marrow (BM) production of invasive Ly6Chigh monocytes. As BM adiposity also accrues with HFD, we explored the relationship between the gains in BM white adipocytes and invasive Ly6Chigh monocytes in vivo and through ex vivo paradigms. We find a temporal and causal link between BM adipocyte whitening and the Ly6Chigh monocyte surge, preceding the adipose tissue macrophage rise during HFD. Phenocopying this, ex vivo treatment of BM cells with conditioned media from BM adipocytes or from bona fide white adipocytes favoured Ly6Chigh monocyte preponderance. Notably, Ly6Chigh skewing was preceded by monocyte metabolic reprogramming towards glycolysis, reduced oxidative potential and increased mitochondrial fission. In sum, short-term HFD changes BM cellularity, resulting in local adipocyte whitening driving a gradual increase and activation of invasive Ly6Chigh monocytes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Parastoo Boroumand

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. David C Prescott

    Department of Immunology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Tapas Mukherjee

    Department of Immunology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Philip J Bilan

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael Wong

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Jeff Shen

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Ivan Tattoli

    Department of Laboratory Medicine and Pathopysiology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Yuhuan Zhou

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Angela Li

    Research Institute, Toronto General Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Tharini Sivasubramaniyam

    Research Institute, Toronto General Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Nan Shi

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Lucie Y Zhu

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1048-5377
  13. Zhi Liu

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Clinton Robbins

    Department of Laboratory Medicine and Pathophysiology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Dana J Philpott

    Department of Immunology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  16. Stephen E Girardin

    Department of Immunology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Amira Klip

    Cell Biology Program, Hospital for Sick Children, Toronto, Canada
    For correspondence
    amira@sickkids.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7906-0302

Funding

Canadian Institutes of Health Research FDN-143203 (FDN-143203)

  • Amira Klip

Canadian Institutes of Health Research FDN-14333 (FDN-14333)

  • Dana J Philpott

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

Ethics

Animal experimentation: Mouse protocols followed the strictest protocols dictated by the Canadian Institutes of Health Research guidelines and were approved by the animal care committee (Protocol #20011850 to S.E.G. and 483 D.J.P., University of Toronto; and #1000047074 to A.K., The Hospital for Sick Children).

Copyright

© 2022, Boroumand 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.

Metrics

  • 2,342
    views
  • 493
    downloads
  • 20
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Parastoo Boroumand
  2. David C Prescott
  3. Tapas Mukherjee
  4. Philip J Bilan
  5. Michael Wong
  6. Jeff Shen
  7. Ivan Tattoli
  8. Yuhuan Zhou
  9. Angela Li
  10. Tharini Sivasubramaniyam
  11. Nan Shi
  12. Lucie Y Zhu
  13. Zhi Liu
  14. Clinton Robbins
  15. Dana J Philpott
  16. Stephen E Girardin
  17. Amira Klip
(2022)
Bone marrow adipocytes drive the development of tissue invasive Ly6Chigh monocytes during obesity
eLife 11:e65553.
https://doi.org/10.7554/eLife.65553

Share this article

https://doi.org/10.7554/eLife.65553

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.

    1. Immunology and Inflammation
    Zhiyan Wang, Nore Ojogun ... Mingfang Lu
    Research Article

    The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.