Endocrine Abstracts

Background: Alström Syndrome (AS) is a rare autosomal recessive disease featuring highly accelerated insulin resistance, fatty liver, diabetes and heart failure among other syndromic features. Heart failure leads to significant early mortality, but is complex and likely multifactorial, with developmental defects, accelerated atherosclerosis, and fibrosis all implicated. These cardiometabolic complications occur in the face of only moderate obesity in many patients. AS is caused by biallelic loss-of-function mutations in the ALMS1 gene, encoding a large centrosomal protein. The precise derangement of centrosomal and/or primary ciliary function caused by loss of ALMS1 is unknown. There is currently no specific treatment for AS. Further research is needed to address this unmet clinical need. Several global knockout (KO) mouse models have been described to recapitulate key metabolic components of AS, but none have characterised cardiac function in-vivo, and tissue-specific KO approaches have not yet been used to tease out contributions of different cell types to pathology.

Hypothesis: The metabolic profile of AS closely resembles that of lipodystrophy. We thus hypothesised that loss of Alms1 function in mesenchymal stem cell populations, such as adipose precursor cells, would recapitulate the metabolic derangement in AS. We secondarily hypothesised that this would mitigate some but not all cardiac complications.

Methods: A novel global KO mouse was generated by crossing the EUCOMM Tm1c Alms1 line with the global CAG-Cre driver. A Pdgfrα-Cre driver was used to abrogate Alms1 function only in mesenchymal progenitor cells and their descendants including preadipocytes and adipocytes. We undertook metabolic phenotyping and echocardiography of global and Pdgfrα+ Alms1-KO mouse models in both sexes on a 45% high-fat diet.

Results: Consistent with previous models and the human disease, global Alms1 KO mice were hyperphagic, obese, insulin resistant, and had severe hepatosteatosis. We show novel evidence of restrictive cardiomyopathy in 23-week-old female global KO mice, manifesting as increased left-atrial area and decreased intraventricular relaxation time. This was not seen in male global KO mice. Initial assessment did not reveal cardiac apical fibrosis on histological examination. KO of Alms1 only in MSCs and their descendants recapitulated key metabolic phenotypes of global KO animals including obesity and insulin resistance. Interestingly hyperphagia was also seen despite lack of neuronal Alms1 KO.

Conclusions: 1. Female-specific restrictive cardiomyopathy is seen in mice deficient in Alms1.

2. MSC-derived lineages are critical in driving the severe metabolic syndrome in AS.

3. Hyperphagia in AS does not depend on neuronal Alms1 deficiency.