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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\n                    <jats:italic>MFN2<\/jats:italic>\n                    , 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,\n                    <jats:italic>\n                      Mfn2\n                      <jats:sup>R707W\/R707W<\/jats:sup>\n                    <\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.7554\/elife.82283","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T06:15:47Z","timestamp":1675232147000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.82283","source":"Crossref","is-referenced-by-count":10,"title":["A mouse model of human mitofusin-2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4711-9215","authenticated-orcid":true,"given":"Jake P","family":"Mann","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge","place":["Cambridge, United 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