Yeo Giles S H
MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Mol Cell Endocrinol. 2014 Nov;397(1-2):34-41. doi: 10.1016/j.mce.2014.09.012. Epub 2014 Sep 16.
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.
全基因组关联研究（GWAS）表明，16号染色体上包含FTO以及IRX3、5、6、FTM和FTL的一个基因座上的单核苷酸多态性（SNP）与人类肥胖密切相关。然而，GWAS本质上是不明确基因的，达到给定表型适当统计阈值的SNP可以出现在基因组的任何位置，在任何编码序列之内、附近或远处。因此，该领域的一个主要挑战是将这些统计学上的发现转化为真正的生物学见解。关键问题是这些基因中哪些与肥胖相关，其潜在机制是什么？由于小鼠和人类中FTO功能丧失突变导致严重生长迟缓，而全球范围内过表达FTO的小鼠肥胖，最初的注意力集中在这个基因上。我们和其他人已经表明，在体外，重组FTO能够催化单链核酸的Fe（II）和2-氧代戊二酸依赖性去甲基化，对RNA有偏好。我们已经表明，FTO的表达受必需氨基酸（AA）调节，并且它通过一种依赖于其去甲基化能力的机制将氨基酸水平与哺乳动物雷帕霉素复合物1（mTORC1）信号传导联系起来。因此，FTO是一种AA传感器，在调节适当的生长和翻译中起关键作用。然而，最近关注FTO内与肥胖相关变体的数据表明，两个相邻基因RPGRIP1L和IRX3在SNP与观察到的人类表型之间存在功能联系。与Fto一样，在小鼠中干扰这些基因的表达会导致体重表型，Irx3纯合缺失导致小鼠体型变小，Rpgrip1l杂合缺失导致轻度肥胖表型。因此，该区域的许多基因可能在决定身体组成方面起重要作用。
