The role of the FTO (Fat Mass and Obesity Related) locus in regulating body size and composition.

Genomewide association studies (GWAS) have indicated that SNPs on a chromosome 16 locus encompassing FTO, as well as IRX3, 5, 6, FTM and FTL are robustly associated with human obesity. GWAS, however, are by nature gene agnostic, and SNPs reaching the appropriate statistical threshold for a given phenotype can appear anywhere in the genome, within, near or far away from any coding sequence. Thus a major challenge in the field has been to translate these statistical hits into real biological insight. The key question is which of these genes are responsible for the association with obesity, and what is the underlying mechanism? With loss of function FTO mutations in both mice and humans resulting in severe growth retardation and mice globally over-expressing FTO being obese, the initial attention was focussed on this gene. We and others have shown that in vitro, recombinant FTO is able to catalyse the Fe(II)- and 2OG-dependent demethylation of single stranded nucleic-acids, with a preference for RNA. We have shown that FTO expression is regulated by essential amino acids (AAs) and that it couples amino acid levels to mammalian Target of Rapamycin Complex 1 (mTORC1) signalling, through a mechanism dependent on its ability to demethylate. Thus FTO is an AA sensor and plays a key role regulating appropriate growth and translation. However, recent data focussing on obesity associated variants within FTO have implicated two neighbouring genes, RPGRIP1L and IRX3, as having a functional link between the SNP and the observed human phenotypes. As with Fto, perturbing the expression of these genes in mice results in a bodyweight phenotype, with homozygous deletion of Irx3 resulting in a smaller mouse and heterozygous deletion of Rpgrip1l leading to a mild obesity phenotype. Thus it may be that a number of genes in this region play an important role in determining body composition.