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

John Curtin School of Medical Research (T.A., D.G.S., C.G.V., C.C.G.), The Australian National University, and The Canberra Hospital and The Australian National University Medical School (T.A., D.G.S.), Canberra ACT 2601, Australia; Monash Institute of Medical Research and The Australian Research Council Centre of Excellence in Biotechnology and Development (M.K.O., C.K., D.M.d.K.), Monash University, Melbourne, Victoria 3168. Australia; Garvan Institute of Medical Research (A.S., N.J.L.), Sydney, New South Wales 2010, Australia; Murdoch Childrens Research Institute (S.S.M.M.), Royal Children’s Hospital, Melbourne, Victoria 3052, Australia; Phenomix Australia Pty Ltd (K.N., C.L.), and The Australian Phenomics Facility (C.C.G.), Canberra ACT 2601, Australia; and Flinders Medical Centre and Flinders University (N.P.), Bedford Park, Adelaide, South Australia 5042, Australia

Address all correspondence and requests for reprints to: Dr. Todor Arsov, Immunogenomics Laboratory, John Curtin School of Medical Research, Australian National University, Mills Road, P.O. Box 334, Canberra ACT 2601, Australia. E-mail: todor.arsov{at}anu.edu.au.

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.

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