Karra, E; (2014) The role of the fat mass and obesity-associated gene in appetite regulation. Doctoral thesis , UCL (University College London).

Abstract

FTO encodes a nucleic acid demethylase with substrate preference towards N6-methyladenosisne (m6A). Variation in the FTO gene confers the single greatest genetic risk for common obesity amongst all obesity susceptibility loci identified to date. The mechanisms via which FTO variation promotes adiposity remain unknown. Increased hunger, increased energy intake, and enhanced preference for palatable, calorically-rich foods constitute a common denominator between ghrelin signalling and FTO perturbation. Hence, we hypothesized that altered ghrelin levels mediate the FTO-related obesogenic feeding patterns, and we undertook human, rodent and cellular studies to test our hypothesis. Here we show that Caucasian males, homozygous for the high-risk allele A of FTO rs9939609 exhibit increased BMI and adiposity compared to homozygotes for the protective variant T, even within the normal BMI-spectrum; before the development of overweight and obesity. In two independent cohorts we show that normal-BMI AA subjects exhibit attenuated hunger suppression post-meal and aberrant ghrelin profile compared to adiposity-matched TT controls; with the ghrelin phenotype of normal-BMI AA subjects reminiscing ghrelin changes seen in human obesity. Moreover, we show that global Fto deletion in mice results in alterations in circulating ghrelin levels. Utilizing reward-trait assessment questionnaires we demonstrate weight-independent increases in reward responsiveness in AA subjects. Using fMRI we show that FTO genotype weight-independently alters neuronal responsiveness to visual food cues within homeostatic and reward appetitive circuitries. Furthermore, we report that peripheral blood cells from healthy normal-weight Caucasian AA males have increased FTO and GHRL mRNA relative abundance, with decreased m6A GHRL mRNA residues compared to TT controls. Finally, we show that overexpression of FTO in HeLa cells increases abundance of pre-proghrelin, pro-ghrelin and ghrelin peptides, as well as GOAT protein in the cell lysates. Collectively, these data reveal a novel link between FTO and ghrelin, and implicate ghrelin deregulation to the adipogenic effects of FTO.

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