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Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human <jats:italic>MFN2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> fibroblasts, and in <jats:italic>Mfn2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Forcing galactose metabolism in human <jats:italic>MFN2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on <jats:italic>Mfn2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in <jats:italic>Mfn2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female <jats:italic>Mfn2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup>\n              <jats:italic>mice<\/jats:italic>, and serum lactate in males. Rapamycin \u2013 a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of <jats:italic>Mfn2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> preadipocytes. In male <jats:italic>Mfn2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in <jats:italic>Mfn2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R707W\/R707W<\/jats:italic>\n              <\/jats:sup> preadipocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Ethanol mildly exacerbates murine <jats:italic>MFN2<\/jats:italic>-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s10020-025-01314-2","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T14:00:29Z","timestamp":1754316029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical evaluation of candidate \u201ckill or cure\u201d strategies to treat MFN2-related lipodystrophy"],"prefix":"10.1186","volume":"31","author":[{"given":"Ineke","family":"Luijten","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Weng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ula","family":"Kibildyte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Buchan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ami","family":"Onishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jake","family":"Mann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanor","family":"McKay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Savage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"issue":"12","key":"1314_CR1","doi-asserted-by":"publisher","first-page":"e28536","DOI":"10.1371\/journal.pone.0028536","volume":"6","author":"C Aguer","year":"2011","unstructured":"Aguer C, et al. 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Adam, et al., Editors. 1993: Seattle (WA)."}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01314-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-025-01314-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01314-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T13:30:51Z","timestamp":1757338251000},"score":1,"resource":{"primary":{"URL":"https:\/\/molmed.biomedcentral.com\/articles\/10.1186\/s10020-025-01314-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1314"],"URL":"https:\/\/doi.org\/10.1186\/s10020-025-01314-2","relation":{},"ISSN":["1528-3658"],"issn-type":[{"type":"electronic","value":"1528-3658"}],"subject":[],"published":{"date-parts":[[2025,8,4]]},"assertion":[{"value":"8 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Dermal fibroblasts were derived from skin biopsies from healthy volunteers and three people with biallelic MFN2 mutations as previously described (Rocha ). Informed consent was obtained and confirmed in writing as part of studies approved by the UK National Research Ethics Committee (studies 18\/EE\/0068 and 12\/EE\/0405). All animal experiments were performed under UK Home Office Project License P87539BCC, approved by the University of Edinburgh Animal Welfare and Ethical Review Board, and conducted in line with ARRIVE guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Really none are truly competing, but for full disclosure: RKS has received consulting fees from Novartis, Astra Zeneca, and Alnylam, and speaking fees from Novo Nordisk, Eli Lilly, Amryt\/Chiesi, and Medscape.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"273"}}