{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:18:40Z","timestamp":1768508320240,"version":"3.49.0"},"posted":{"date-parts":[[2023,10,13]]},"group-title":"Physiology","reference-count":47,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Alstr\u00f6m Syndrome (AS), a multi-system disease caused by mutations in the\n                    <jats:italic>ALMS1<\/jats:italic>\n                    gene, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and hepatosteatosis. How loss of ALMS1 causes this phenotype is poorly understood, but prior studies have circumstancially implicated impaired adipose tissue expandability. We set out to test this by comparing the metabolic effects of selective\n                    <jats:italic>Alms1<\/jats:italic>\n                    knockout in mesenchymal cells including preadipocytes to those of global\n                    <jats:italic>Alms1<\/jats:italic>\n                    knockout.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Global\n                    <jats:italic>Alms1<\/jats:italic>\n                    knockout (KO) mice were generated by crossing floxed\n                    <jats:italic>Alms1<\/jats:italic>\n                    and CAG-Cre mice. A\n                    <jats:italic>Pdgfr\u03b1<\/jats:italic>\n                    -Cre driver was used to abrogate Alms1 function selectively in mesenchymal stem cells (MSCs) and their descendants, including preadipocytes. We combined metabolic phenotyping of global and\n                    <jats:italic>Pdgfr\u03b1<\/jats:italic>\n                    +\n                    <jats:italic>Alms1<\/jats:italic>\n                    -KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Global\n                    <jats:italic>Alms1<\/jats:italic>\n                    KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver.\n                    <jats:italic>Pdgfr\u03b1<\/jats:italic>\n                    -\n                    <jats:italic>cre<\/jats:italic>\n                    driven KO of\n                    <jats:italic>Alms1<\/jats:italic>\n                    (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female\n                    <jats:italic>Alms1<\/jats:italic>\n                    MSC KO mice. Hyperphagia was not evident in male\n                    <jats:italic>Alms1<\/jats:italic>\n                    MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfr\n                    <jats:italic>\u03b1<\/jats:italic>\n                    expression.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Mesenchymal deletion of\n                    <jats:italic>Alms1<\/jats:italic>\n                    recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role for\n                    <jats:italic>Alms1<\/jats:italic>\n                    in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as a\n                    <jats:italic>forme fruste<\/jats:italic>\n                    of lipodystrophy. Therapies should prioritise targeting positive energy balance.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.10.12.562074","type":"posted-content","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T01:35:16Z","timestamp":1697247316000},"source":"Crossref","is-referenced-by-count":1,"title":["Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alstr\u00f6m Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5690-6042","authenticated-orcid":false,"given":"Eleanor J.","family":"McKay","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ineke","family":"Luijten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Weng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0684-3215","authenticated-orcid":false,"given":"Pablo B.","family":"Martinez de Morentin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elvira","family":"De Frutos Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6663-524X","authenticated-orcid":false,"given":"Zhanguo","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail G.","family":"Kolonin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7731-1419","authenticated-orcid":false,"given":"Lora K.","family":"Heisler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-3069","authenticated-orcid":false,"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023101713300618000_2023.10.12.562074v1.1","first-page":"225","article-title":"Alstrom Syndrome: Genetics and Clinical Overview","volume":"12","year":"2012","journal-title":"Curr. 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