Regulation of adiposity in Drosophila
File(s)
Author(s)
Vincent, Alec Jacques
Type
Thesis
Abstract
Obesity is a complex pathophysiology that is influenced by both cellular and systemic processes, highlighting the importance of in vivo experimental models to study the regulation of adiposity and obesity-associated diseases. Using the genetic tractability of Drosophila, I explore the role of the metabolite asymmetric dimethylarginine (ADMA) in the regulation of adiposity. ADMA levels were experimentally increased in vivo by genetically reducing its metabolic clearance by knocking-out dimethylarginine dimethylaminohydrolase (DDAH). DDAH knock-out animals (DDAHXP) display a range of metabolic phenotypes including a reduction in fat storage, increased mitochondrial content, elevated levels of respiration and altered sleep. Phenotypic differences between DDAHXP and an independently generated DDAH knock-out allele led me to identify an uncharacterised neighbouring gene as a novel putative regulator of adiposity. Knockdown of this gene was associated with downregulation of the aminotransferase dAGXT. In humans, AGXT deficiency is associated with primary hyperoxaluria type 1 (PH1), an autosomal recessive disorder of glyoxylate metabolism. Despite its relevance to human disease, AGXT is almost completely unstudied in Drosophila. I found that knockdown of dAGXT resulted in the formation of renal stones, recapitulating the major pathological feature of PH1. I identified previously uncharacterised short dAGXT transcripts that lack the sequence encoding its putative N-terminal mitochondrial targeting signal. I suggest that differential transcript choice, and hence organelle targeting, could underlie an important regulatory mechanism of metabolic activity. Of relevance, the most common mutations associated with PH1 cause mitochondrial mistargeting. Finally, I develop a model of obesity-associated nephrolithiasis and explore the underlying aetiology. Overall, work here highlights the usefulness of Drosophila as a model to study adiposity and obesity-associated disease.
Version
Open Access
Date Issued
2021-10
Date Awarded
2022-06
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Cocheme, Helena
Leiper, James
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)