Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome

Abstract

AbstractBackgroundAlström Syndrome (AS), a multi-system disease caused by mutations in theALMS1gene, 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 selectiveAlms1knockout in mesenchymal cells including preadipocytes to those of globalAlms1knockout.MethodsGlobalAlms1knockout (KO) mice were generated by crossing floxedAlms1and CAG-Cre mice. APdgfrα-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 andPdgfrα+Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues.ResultsGlobalAlms1KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver.Pdgfrα-credriven KO ofAlms1(MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in femaleAlms1MSC KO mice. Hyperphagia was not evident in maleAlms1MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrαexpression.ConclusionsMesenchymal deletion ofAlms1recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role forAlms1in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as aforme frusteof lipodystrophy. Therapies should prioritise targeting positive energy balance.