RESUMO
SNPs in the first intron of FTO (fat mass and obesity associated) are strongly associated with human obesity. While it is not yet formally established that this effect is mediated through the actions of the FTO protein itself, loss of function mutations in FTO or its murine homologue Fto result in severe growth retardation, and mice globally overexpressing FTO are obese. The mechanisms through which FTO influences growth and body composition are unknown. We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing.
Assuntos
Aminoácidos/metabolismo , Composição Corporal/genética , Obesidade/genética , Proteínas/genética , Proteínas/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Fracionamento Celular , Cromatografia Líquida , Eletroforese em Gel de Poliacrilamida , Fibroblastos , Células HEK293 , Humanos , Imunoprecipitação , Camundongos , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas em TandemRESUMO
Few would dispute that the current obesity epidemic has been driven by lifestyle and environmental changes. However, it is clear that individuals respond differently to these "obesigenic" changes and this variation in response has a strong genetic element. Genome-wide association studies have revealed that single nucleotide polymorphisms in Fat mass and obesity-associated transcript (FTO) are robustly associated with body mass index and obesity. Although the effect of these risk alleles are modest, with heterozygous and homozygous carriers weighing approximately 1.5 and 3 kg more respectively, there are an estimated one billion homozygous carriers in the world, spanning multiple different ethnicities and populations. Yet despite its broad impact, the biological function of FTO, particularly its role in controlling energy balance, remains unknown. Although the study of severe Mendelian obesity has been invaluable in illuminating critical pathways controlling food intake, the major burden of disease is carried by those of us with "common obesity," which to date has resisted yielding meaningful biological insights. FTO has at last given us a handle on a huge, worldwide, common problem. In this review, we focus on the available genetic and in vivo evidence to date that implicates FTO in the control of energy balance.