RT Journal Article
SR Electronic
T1 A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.20.508662
DO 10.1101/2022.09.20.508662
A1 JP Mann
A1 X Duan
A1 A Alvarez-Guaita
A1 A Haider
A1 I Luijten
A1 M Page
A1 S Patel
A1 F Scurria
A1 M Protasoni
A1 LC Tábara
A1 S Virtue
A1 S O’Rahilly
A1 M Armstrong
A1 J Prudent
A1 RK Semple
A1 DB Savage
YR 2022
UL http://biorxiv.org/content/early/2022/09/22/2022.09.20.508662.abstract
AB 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 this selective perturbation of mitochondrial function 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 by 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 perturbs mitochondrial morphology and activates the integrated stress response selectively 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.Competing Interest StatementThe authors have declared no competing interest.