Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome.
| العنوان: | Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome. |
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| المؤلفون: | McKay EJ, Luijten I, Weng X, Martinez de Morentin PB, De Frutos González E, Gao Z, Kolonin MG, Heisler LK, Semple RK |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 13. Date of Electronic Publication: 2023 Oct 13. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Background: Alström Syndrome (AS), a multi-system disease caused by mutations in the ALMS1 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 Alms1 knockout in mesenchymal cells including preadipocytes to those of global Alms1 knockout. Methods: Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα -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 Pdgfrα + Alms1 -KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. Results: Global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα - cre driven KO of Alms1 (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 Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfr α expression. Conclusions: Mesenchymal deletion of Alms1 recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role for Alms1 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 forme fruste of lipodystrophy. Therapies should prioritise targeting positive energy balance. |
| التعليقات: | Update in: Mol Metab. 2024 Apr 6;:101933. (PMID: 38583571) |
| تواريخ الأحداث: | Date Created: 20231024 Latest Revision: 20240418 |
| رمز التحديث: | 20240419 |
| مُعرف محوري في PubMed: | PMC10592792 |
| DOI: | 10.1101/2023.10.12.562074 |
| PMID: | 37873427 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.10.12.562074 |
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