A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Abstract

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.

Data availability

All reagents used are publicly available. Primer sequences and antibodies are detailed in Supplementary Tables 1 and 2. Code used in analysis is available from: https://doi.org/10.5281/zenodo.5770057. Raw counts from transcriptomic analysis are available from GEO with accession number GSE210771.

The following data sets were generated

Article and author information

Author details

  1. Jake P Mann

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4711-9215
  2. Xiaowen Duan

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Satish Patel

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5345-8942
  4. Luis Carlos Tábara

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Fabio Scurria

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Anna Alvarez-Guaita

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Afreen Haider

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Ineke Luijten

    Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Matthew Page

    New Medicines, UCB Pharma, Slough, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Margherita Protasoni

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Koini Lim

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Sam Virtue

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9545-5432
  13. Stephen O'Rahilly

    Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2199-4449
  14. Martin Armstrong

    New Medicines, UCB Pharma, Slough, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Julien Prudent

    Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3821-6088
  16. Robert K Semple

    Medical Research Council Mitochondrial Biology Unit, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    rsemple@exseed.ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6539-3069
  17. David B Savage

    Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    dbs23@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7857-7032

Funding

Wellcome Trust (210752)

  • Robert K Semple

Ramon Areces

  • Luis Carlos Tábara

Wellcome Trust (219417)

  • David B Savage

Wellcome Trust (216329/Z/19/Z)

  • Jake P Mann

Wellcome Trust (214274)

  • Stephen O'Rahilly

Swedish Research Council

  • Ineke Luijten

Medical Research Council (MC_UU_00015/7 and MC_UU_00028/5)

  • Julien Prudent

Medical Research Council (MC_UU_00014/5)

  • Stephen O'Rahilly

Medical Research Council (MRC_MC_UU_12012/5)

  • Stephen O'Rahilly

Wellcome Trust (208363/Z/17/Z)

  • Stephen O'Rahilly

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

Reviewing Editor

  1. Jonathan S Bogan, Yale School of Medicine, United States

Ethics

Animal experimentation: All experiments were performed under UK Home Office-approved Project License 70/8955 except for thermogenic capacity assessments which were conducted under P0101ED1D. Protocols were approved by the University of Cambridge Animal Welfare and Ethical Review Board.

Version history

  1. Received: July 29, 2022
  2. Preprint posted: September 22, 2022 (view preprint)
  3. Accepted: January 30, 2023
  4. Accepted Manuscript published: February 1, 2023 (version 1)
  5. Accepted Manuscript updated: February 2, 2023 (version 2)
  6. Accepted Manuscript updated: February 3, 2023 (version 3)
  7. Version of Record published: February 17, 2023 (version 4)

Copyright

© 2023, Mann 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. Jake P Mann
  2. Xiaowen Duan
  3. Satish Patel
  4. Luis Carlos Tábara
  5. Fabio Scurria
  6. Anna Alvarez-Guaita
  7. Afreen Haider
  8. Ineke Luijten
  9. Matthew Page
  10. Margherita Protasoni
  11. Koini Lim
  12. Sam Virtue
  13. Stephen O'Rahilly
  14. Martin Armstrong
  15. Julien Prudent
  16. Robert K Semple
  17. David B Savage
(2023)
A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion
eLife 12:e82283.
https://doi.org/10.7554/eLife.82283

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https://doi.org/10.7554/eLife.82283

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