FTO and appetite regulation. (360G-Wellcome-093774_Z_10_Z)

A single nucleotide polymorphism, rs9939609, in the first intron of the fat mass- and obesity associated gene (FTO) confers the greatest genetic risk for obesity. Subjects homozygous for the at-risk A allele exhibit reduced satiety, increased energy intake and energy-dense food preference. The mechanisms underlying these obesity-prone eating patterns remain unknown. Hypothesising a link between FTO and the gut hormone system, I undertook studies to investigate this. I found that non-obese human subjects carrying the A allele have increased reward responsiveness, an obesity-prone behaviour. Moreover, AA subjects exhibited an attenuated reduction in postprandial hunger and aberrant suppression of the hunger hormone ghrelin. In mice, I found that gastrointestinal FTO expression and circulating ghrelin levels are positively correlated suggesting a regulatory role for FTO on ghrelin. I now wish to build upon these findings with key goals of the proposed work being to investigate: i) the neurobiological effects of FTO rs9939609 using fMRI. ii) the regulatory relationship between FTO and ghrelin. iii) the effect of FTO rs9969309 on appetite and gut hormones in obese patients. The proposed work will offer insights into how FTO results in obesity and may result in the development of genotype-tailored treatment strategies for the at-risk population.