Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
The Rowett Institute, University of Aberdeen, Aberdeen, UK; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
Mol Metab. 2024 Jun;84:101933. doi: 10.1016/j.molmet.2024.101933. Epub 2024 Apr 6.
Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout.
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 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.
Assessed on 45% fat diet to promote adipose expansion, 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 Pdgfrα expression.
Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including 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. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.
由双等位基因 ALMS1 突变引起的 Alström 综合征（AS）包括肥胖伴严重胰岛素抵抗性糖尿病、血脂异常和脂肪肝。先前的研究表明，下丘脑神经元中 ALMS1 功能的丧失导致了摄食过度，而不成比例的代谢并发症可能是由于脂肪组织扩展性受损所致。我们通过比较全球和间充质干细胞（MSC）特异性 Alms1 敲除的代谢影响来验证这一点。
通过杂交 floxed Alms1 和 CAG-Cre 小鼠产生了全局 Alms1 敲除（KO）小鼠。使用 Pdgfrα-Cre 驱动来选择性地消除 MSC 及其后代（包括前脂肪细胞）中的 Alms1 功能。我们将全球和 Pdgfrα+ Alms1-KO 小鼠的代谢表型结合在 45%脂肪饮食中进行评估，同时测量身体成分和食物摄入量，并对代谢组织进行组织学分析。
在 45%脂肪饮食中评估以促进脂肪扩张时，全局 Alms1 KO 导致摄食过度、肥胖、胰岛素抵抗、血脂异常和脂肪肝。Pdgfrα-cre 驱动的 Alms1（MSC KO）敲除重现了胰岛素抵抗、脂肪肝和血脂异常，在两性中均如此。其他表型存在性别二态性：只有在雌性 Alms1 MSC KO 小鼠中才存在脂肪量增加。雄性 Alms1 MSC KO 小鼠中没有发现摄食过度，但在 MSC KO 雌性中发现了摄食过度，尽管神经元中没有 Pdgfrα 表达。
MSC 中 Alms1 的缺失重现了 AS 的代谢特征，包括脂肪肝。这证实了 Alms1 在脂肪谱系中的关键作用，其缺失足以导致全身代谢效应和对远程器官的损害。雌性的摄食过度可能取决于少突胶质前体细胞而不是神经元中的 Alms1 缺乏。AS 应被视为脂肪营养不良的顿挫型。
