The continuous rise of obesity and its co-morbidities are a matter of grave concern to health services across the globe. Genome wide association studies have identified the fat mass and obesity associated (FTO) gene locus as having one of the most robust effects on body weight, due to increased food intake and preference for high energy foods. Allelic variants associated with obesity differ in single-nucleotide polymorphisms in the first intron of the FTO gene. Mice studies and human genomic data from recent years have implicated several genes in this locus, nevertheless, FTO remains the strongest candidate gene to contribute to the obesogenic phenotype. Furthermore, a recent study identified FTO as a potential regulator of ghrelin expression, and a modulator of ghrelin’s actions in the brain, suggesting a candidate mechanism through which FTO may influence energy homeostasis.
The first aim of this project was to determine if FTO acts in a cell-autonomous manner to regulate the expression and production of ghrelin, thereby affecting energy homeostasis. Secondly, we aimed to investigate if FTO modulates the actions of ghrelin upon feeding behaviour in two neuronal populations; the dopaminergic (DA) and the AgRP neurones.
The results here presented demonstrate that FTO overexpression in ghrelin-producing cells impairs nutrient regulation of ghrelin release, affecting adiposity, food intake and increased susceptibility to an obesogenic diet. Moreover, targeted overexpression of FTO in DA neurones enhances sensitivity to ghrelin in feeding responses and behaviour. Lastly, overexpression of FTO in AgRP neurones causes increased adiposity and body weight gain, without significantly altering feeding response to ghrelin.
The mouse models in this thesis recapitulate human phenotypes of FTO obesity-risk carriers, thereby providing useful tools to study the precise mechanisms underlying the role of FTO in influencing energy homeostasis.