Drosophila melanogaster as a high-throughput and in vivo model to study body weight and feeding behaviour

Obesity and its associated comorbidities represent one of the greatest public health challenges of the 21st century. Whilst the increase in prevalence has been driven by changes in lifestyle and environment, it is clear that there is a genetic component underlying the variation in body weight between individuals. However, the speed of translating obesity genetics into insightful biological knowledge has not kept pace with the rate of identification of potential genes of interest. One reason for this is that studies have so far been addressed in complex model organisms such as mice. Drosophila melanogaster is a key model for research in developmental biology, cell biology and neurobiology, and has also recently been demonstrated to be an excellent model for dissecting metabolic homeostasis pathways. In this thesis, a suite of assays was developed in Drosophila to examine changes in the state of energy homeostasis and changes in energy intake in response to specific genetic perturbations. This screen was validated by its ability to detect metabolic perturbation in wild-type flies, and to differentiate between positive and negative control genes. Different Drosophila models were investigated for their suitability for the screen, and neuron-specific RNAi was found to provide the most useful information. CRISPR was also investigated as a method of generating mutations in target genes de novo. The validated screen was then used to explore genes highlighted by GWAS studies of human body mass index (BMI), and by transcriptomics studies of fasted mouse hypothalamic neurons. Each of these screens identified some genes which are already known to play an important role in the control of energy homeostasis in mammals, demonstrating that the screen is able to produce relevant results. They also highlighted several genes for which there is currently no published functional data, demonstrating the utility of Drosophila in a high-throughput screen to assay the potential involvement of genes in the neuronal control of food intake and body weight.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Chalmers, Jennifer

Advisor dc:contributor.advisor

• Yeo, Giles

• Obesity
• genetics
• Drosophila
• GWAS
• RNAseq
• Screen

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/83c61269-85cb-4e29-9fe5-81ced0585ddd/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.39064

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/291906