PDF(Pubmed)
Abstract：
OBJECTIVE: 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.
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 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: 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.
CONCLUSIONS: 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.
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 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: 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.
CONCLUSIONS: 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.
摘要：
目标：Alström综合征（AS），由双等位基因ALMS1突变引起，包括肥胖与不成比例的严重胰岛素抵抗糖尿病，血脂异常,和脂肪肝。先前的研究表明，下丘脑神经元ALMS1功能的丧失是吞食过多的原因，而不成比例的代谢并发症可能是由于脂肪组织扩张性受损。我们通过比较全局和间充质干细胞（MSC）特异性Alms1敲除的代谢作用来测试这一点。
方法:全局Alms1敲除(KO)小鼠是通过杂交漂浮的Alms1和CAG-Cre小鼠产生的。使用Pdgfrα-Cre驱动器选择性地消除MSC及其后代中的Alms1功能，包括前脂肪细胞。我们将45％脂肪饮食中的全球和PdgfrαAlms1-KO小鼠的代谢表型与身体成分和食物摄入量的测量相结合，和代谢组织的组织学分析。
结果：评估了45%脂肪饮食促进脂肪扩张，全球Alms1KO引起饮食亢进，肥胖，胰岛素抵抗，血脂异常,和脂肪肝。Pdgfrα-cre驱动的Alms1KO（MSCKO）概述了胰岛素抵抗，脂肪肝,两性的血脂异常.其他表型是性二态的：仅在雌性Alms1MSCKO小鼠中存在脂肪量增加。在雄性Alms1MSCKO小鼠中，饮食过度不明显，但在MSCKO雌性中发现，尽管没有神经元Pdgfrα表达。
结论：Alms1的间充质缺失概括了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，其损失足以引起全身代谢作用和对远程器官的损害。女性的饮食过多可能取决于少突胶质细胞前体细胞而不是神经元的Alms1缺乏。AS应被视为脂肪营养不良的形式。
方法:全局Alms1敲除(KO)小鼠是通过杂交漂浮的Alms1和CAG-Cre小鼠产生的。使用Pdgfrα-Cre驱动器选择性地消除MSC及其后代中的Alms1功能，包括前脂肪细胞。我们将45％脂肪饮食中的全球和PdgfrαAlms1-KO小鼠的代谢表型与身体成分和食物摄入量的测量相结合，和代谢组织的组织学分析。
结果：评估了45%脂肪饮食促进脂肪扩张，全球Alms1KO引起饮食亢进，肥胖，胰岛素抵抗，血脂异常,和脂肪肝。Pdgfrα-cre驱动的Alms1KO（MSCKO）概述了胰岛素抵抗，脂肪肝,两性的血脂异常.其他表型是性二态的：仅在雌性Alms1MSCKO小鼠中存在脂肪量增加。在雄性Alms1MSCKO小鼠中，饮食过度不明显，但在MSCKO雌性中发现，尽管没有神经元Pdgfrα表达。
结论：Alms1的间充质缺失概括了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，其损失足以引起全身代谢作用和对远程器官的损害。女性的饮食过多可能取决于少突胶质细胞前体细胞而不是神经元的Alms1缺乏。AS应被视为脂肪营养不良的形式。
