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).

Reviewing Editor

  1. Florent Ginhoux, Agency for Science Technology and Research, Singapore

Version history

  1. Received: December 7, 2020
  2. Preprint posted: December 9, 2020 (view preprint)
  3. Accepted: September 6, 2022
  4. Accepted Manuscript published: September 20, 2022 (version 1)
  5. Version of Record published: September 26, 2022 (version 2)

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

  • 1,701
    Page views
  • 413
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Yijun Zhang, Tao Wu ... Li Wu
    Research Article

    Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    David J Torres, Paulus Mrass ... Judy L Cannon
    Research Article Updated

    T cells are required to clear infection, and T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of T cells moving in multiple murine tissues using microscopy. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within the villi of small intestine and lung under different activation conditions. Our motility analysis found that while the speeds and the overall displacement of T cells vary within all tissues analyzed, T cells in all tissues tended to persist at the same speed. Interestingly, we found that T cells in the lung show a marked population of T cells turning at close to 180o, while T cells in lymph nodes and villi do not exhibit this “reversing” movement. T cells in the lung also showed significantly decreased meandering ratios and increased confinement compared to T cells in lymph nodes and villi. These differences in motility patterns led to a decrease in the total volume scanned by T cells in lung compared to T cells in lymph node and villi. These results suggest that the tissue environment in which T cells move can impact the type of motility and ultimately, the efficiency of T cell search for target cells within specialized tissues such as the lung.