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Title: Characterizing the function of the Arl15 gene and its role in the development of metabolic traits
Author: Bai, Ying
ISNI:       0000 0004 7966 3658
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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The ARL15 human Genome Wide Association (GWA) locus is associated with increased risk of type 2 diabetes, lower plasma adiponectin, higher fasting plasma insulin, sexually dimorphic altered body composition, lower HDL cholesterol and lipodystrophy. Knocking down ARL15 in a human β cell line is reported to result in impaired insulin secretion. ARL15 belongs to the small GTPase ARF family and is predicted to be involved in vesicle trafficking. The aim of this thesis was to test the Arl15 gene as a functional candidate for metabolic traits. Subcellular localisation studies using overexpression of tagged ARL15 and subcellular ultracentrifugation proved that ARL15 is predominantly localized to the Golgi apparatus. Knocking down full-length Arl15 (Arl15-201) in preadipocytes reduced cell proliferation, resulting in increased differentiation following induction, suggesting that Arl15-201 has a role in cell cycle control during early differentiation. In addition, adiponectin protein levels increased significantly from Day 5 of differentiation with altered assembly of adiponectin oligomer. CRISPR/Cas9 germline knockout of Arl15 showed that homozygous KO mice die postnatally due to a complete cleft palate while heterozygous KO female mice have reduced fat mass on a normal diet. On an HFD KO female mice have reduced body weight, gonadal fat depot weight, brown adipose tissue weight and plasma adiponectin levels. Heterozygous KO mice have altered insulin secretion, normal insulin sensitivity and unaltered glucose homeostasis. Investigation of homozygous Arl15 KO in adult adipose tissue generated by crossing to adiponectin Cre showed no consistent phenotype which may be due to problems with the Cre, which is still being evaluated, or to deletion occurring only in mature adipocytes. In summary my data supports Arl15 as a candidate vesicle trafficking gene for craniofacial development, regulation of plasma adiponectin levels and sexually dimorphic altered body composition. The in vitro studies show a role for Arl15 in adipose tissue development.
Supervisor: Cox, Roger Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available