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.
-
RNAseq from Mfn2-R707W knock-in miceNCBI Gene Expression Omnibus, GSE210771.
Article and author information
Author details
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 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.
Reviewing Editor
- Jonathan S Bogan, Yale School of Medicine, United States
Version history
- Received: July 29, 2022
- Preprint posted: September 22, 2022 (view preprint)
- Accepted: January 30, 2023
- Accepted Manuscript published: February 1, 2023 (version 1)
- Accepted Manuscript updated: February 2, 2023 (version 2)
- Accepted Manuscript updated: February 3, 2023 (version 3)
- 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.
Metrics
-
- 1,310
- Page views
-
- 230
- Downloads
-
- 0
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
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)
Further reading
-
- Cell Biology
- Structural Biology and Molecular Biophysics
Previously we showed that 2D template matching (2DTM) can be used to localize macromolecular complexes in images recorded by cryogenic electron microscopy (cryo-EM) with high precision, even in the presence of noise and cellular background (Lucas et al., 2021; Lucas et al., 2022). Here, we show that once localized, these particles may be averaged together to generate high-resolution 3D reconstructions. However, regions included in the template may suffer from template bias, leading to inflated resolution estimates and making the interpretation of high-resolution features unreliable. We evaluate conditions that minimize template bias while retaining the benefits of high-precision localization, and we show that molecular features not present in the template can be reconstructed at high resolution from targets found by 2DTM, extending prior work at low-resolution. Moreover, we present a quantitative metric for template bias to aid the interpretation of 3D reconstructions calculated with particles localized using high-resolution templates and fine angular sampling.
-
- Cell Biology
- Immunology and Inflammation
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.