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. LuisCa C Tábara

    Medical Research Council Mitochondrial Biology Unit, 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

    Medical Research Council Mitochondrial Biology Unit, 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 I 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

  • LuisCa C Tábara

Wellcome Trust (219417)

  • David B Savage

Wellcome Trust (216329/Z/19/Z)

  • Jake P Mann

Wellcome Trust (214274)

  • Stephen I 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 I O'Rahilly

Medical Research Council (MRC_MC_UU_12012/5)

  • Stephen I O'Rahilly

Wellcome Trust (208363/Z/17/Z)

  • Stephen I O'Rahilly

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 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.

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.

Metrics

  • 1,651
    views
  • 273
    downloads
  • 2
    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. Jake P Mann
  2. Xiaowen Duan
  3. Satish Patel
  4. LuisCa C 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 I 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

Share this article

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

Further reading

    1. Cell Biology
    Satoshi Ninagawa, Masaki Matsuo ... Kazutoshi Mori
    Research Advance

    How the fate (folding versus degradation) of glycoproteins is determined in the endoplasmic reticulum (ER) is an intriguing question. Monoglucosylated glycoproteins are recognized by lectin chaperones to facilitate their folding, whereas glycoproteins exposing well-trimmed mannoses are subjected to glycoprotein ER-associated degradation (gpERAD); we have elucidated how mannoses are sequentially trimmed by EDEM family members (George et al., 2020; 2021 eLife). Although reglucosylation by UGGT was previously reported to have no effect on substrate degradation, here we directly tested this notion using cells with genetically disrupted UGGT1/2. Strikingly, the results showed that UGGT1 delayed the degradation of misfolded substrates and unstable glycoproteins including ATF6α. An experiment with a point mutant of UGGT1 indicated that the glucosylation activity of UGGT1 was required for the inhibition of early glycoprotein degradation. These and overexpression-based competition experiments suggested that the fate of glycoproteins is determined by a tug-of-war between structure formation by UGGT1 and degradation by EDEMs. We further demonstrated the physiological importance of UGGT1, since ATF6α cannot function properly without UGGT1. Thus, our work strongly suggests that UGGT1 is a central factor in ER protein quality control via the regulation of both glycoprotein folding and degradation.

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Senem Ntourmas, Martin Sachs ... Dominic B Bernkopf
    Research Article

    Activation of the Wnt/β-catenin pathway crucially depends on the polymerization of dishevelled 2 (DVL2) into biomolecular condensates. However, given the low affinity of known DVL2 self-interaction sites and its low cellular concentration, it is unclear how polymers can form. Here, we detect oligomeric DVL2 complexes at endogenous protein levels in human cell lines, using a biochemical ultracentrifugation assay. We identify a low-complexity region (LCR4) in the C-terminus whose deletion and fusion decreased and increased the complexes, respectively. Notably, LCR4-induced complexes correlated with the formation of microscopically visible multimeric condensates. Adjacent to LCR4, we mapped a conserved domain (CD2) promoting condensates only. Molecularly, LCR4 and CD2 mediated DVL2 self-interaction via aggregating residues and phenylalanine stickers, respectively. Point mutations inactivating these interaction sites impaired Wnt pathway activation by DVL2. Our study discovers DVL2 complexes with functional importance for Wnt/β-catenin signaling. Moreover, we provide evidence that DVL2 condensates form in two steps by pre-oligomerization via high-affinity interaction sites, such as LCR4, and subsequent condensation via low-affinity interaction sites, such as CD2.