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

Eleanor J McKay; Ineke Luijten; Xiong Weng; Pablo B Martinez de Morentin; Elvira De Frutos González; Zhanguo Gao; Mikhail G Kolonin; Lora K Heisler; Robert K Semple

doi:10.1016/j.molmet.2024.101933

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

Mol Metab. 2024 Apr 6:84:101933. doi: 10.1016/j.molmet.2024.101933. Online ahead of print.

Authors

Eleanor J McKay¹, Ineke Luijten¹, Xiong Weng¹, Pablo B Martinez de Morentin², Elvira De Frutos González³, Zhanguo Gao⁴, Mikhail G Kolonin⁴, Lora K Heisler⁵, Robert K Semple⁶

Affiliations

¹ Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
² The Rowett Institute, University of Aberdeen, Aberdeen, UK; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
³ The Rowett Institute, University of Aberdeen, Aberdeen, UK; Área de Fisiología Humana, Departamento de Ciencias básicas de la Salud, Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcón, Madrid, Spain.
⁴ Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
⁵ The Rowett Institute, University of Aberdeen, Aberdeen, UK.
⁶ Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. Electronic address: rsemple@ed.ac.uk.

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.

Keywords: Adipose tissue; Alms1; Alström syndrome; Diabetes; Insulin resistance; Mouse.