The foz/foz mouse is a murine model of Alstr{u00F6}m syndrome, a monogenetic disorder characterised in humans by childhood obesity, hearing loss, blindness, hyperinsulinaemia, early-onset type 2 diabetes and liver disease. In 2006, research from the host laboratory reported that foz/foz mice inherit a spontaneous mutation (foz) , an 11 base pair deletion in exon 8 of the Alms1 gene, and develop a similar phenotype to patients suffering from Alstr{u00F6}m syndrome. Thus, foz/foz mice are obese

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... d exhibit high circulating insulin and leptin levels as well as fatty liver disease and metabolic syndrome. The purpose of the studies presented in this thesis was to further characterise the pathogenesis of obesity in foz/foz mice, by studying the role of Alms1 and hypothalamic appetite-regulating neuropeptide expression during the development of obesity. ALMS1 has been shown to localise at the base of primary cilia in what is termed the basal body or centrosome. Primary cilia are ubiquitously expressed hair-like organelles. Therefore, the first approach was to study primary cilia in the hypothalamus as well as hypothalamic Alms1 gene expression and Alms1 localisation in foz/foz and wildtype (WT) mice from birth until the obese phenotype is evident. At birth, foz/foz mice showed similar number of ciliated hypothalamic neurons to WT mice. However, from weaning and onwards the number of cilia was significantly decreased in foz/foz mice. In addition, while cilia were present in primary neuronal cultures from foz/foz and WT mice, Alms1 was only detected in WT neurons, appearing as two perinuclear dots at the base of cilia. After weaning, serum leptin levels become greatly elevated in foz/foz compared to WT mice. Leptin decreases appetite by acting in the hypothalamus and inducing or inhibiting the release of appetite-regulating neuropeptides. A detailed study of key hypothalamic neuropeptides demonstrated no differences in their gene and/or protein expression or localisation between foz/foz and WT mice. This failure of elevat [...]