Fat Aussie—A New Alström Syndrome Mouse Showing a Critical Role for ALMS1 in Obesity, Diabetes, and Spermatogenesis

Abstract

Mutations in the human ALMS1 gene are responsible for Alström syndrome, a disorder in which key metabolic and endocrinological features include childhood-onset obesity, metabolic syndrome, and diabetes, as well as infertility. ALMS1 localizes to the basal bodies of cilia and plays a role in intracellular trafficking, but the biological functions of ALMS1 and how these relate to the pathogenesis of obesity, diabetes, and infertility remain unclear. Here we describe a new mouse model of Alström syndrome, fat aussie, caused by a spontaneous mutation in the Alms1 gene. Fat aussie (Alms1 foz/foz) mice are of normal weight when young but, by 120 d of age, they become obese and hyperinsulinemic. Diabetes develops in Alms1 foz/foz mice accompanied by pancreatic islet hyperplasia and islet cysts. Female mice are fertile before the onset of obesity and metabolic syndrome; however, male fat aussie mice are sterile due to a progressive germ cell loss followed by an almost complete block of development at the round-to-elongating spermatid stage of spermatogenesis. In conclusion, Alms1 foz/foz mouse is a new animal model in which to study the pathogenesis of the metabolic and fertility defects of Alström syndrome, including the role of ALMS1 in appetite regulation, pathogenesis of the metabolic syndrome, pancreatic islet physiology, and spermatogenesis.

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

“…Blobby mice exhibit obesity, hyperinsulinemia and dyslipidemia on a chow diet Female Alms1 mutant mice anecdotally exhibit infertility following the onset of obesity (Arsov et al, 2006) (Australian Phenome Bank, personal communication); however, the underlying reason for this infertility is unknown. We used the Blobby (bbb/bbb) mouse strain to characterize the metabolic defects in females and to determine whether there are defects in ovulation and/or oocyte quality that contribute to their obesity-induced sub-fertility.…”

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

“…In our search to explain how deletion of the same gene could produce a nearly opposite phenotype in two different laboratories, we surveyed expression of genes near the Fabp1 locus and surrounding obesity-related QTLs, including some genes ( Alms1, Retstat, Aqp1 ) that have been implicated in metabolic adaptations and body weight maintenance (28)(29)(30)(31)(32)(33). No evidence was found for gene duplication or altered expression of modifi er genes in this region in our L-Fabp Ϫ / Ϫ mice.…”

Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy

“…Bbs1-4, Bbs6-8, Bbs9, and Bbs11 are all expressed during mouse adipogenesis (76), suggesting they may play a role in the generation of fat tissue. Other ciliary proteins have also been implicated in this process, including retinitis-pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L), which localizes to the basal body (77) and whose expression is decreased in the adipose tissue of mutants for the adjacent FTO gene (78) and the Alström syndrome gene ALMS1, for which obese knockout mice have been generated (79,80). The ALMS1 protein, which localizes to the basal body (81,82), is expressed in the early phases of adipogenesis and may be involved in the conversion of preadipocytes to adipocytes (83).…”