Obesity-associated variants within FTO form long-range functional connections with IRX3

摘要

搜寻肥胖的基因原因的工作将FTo基因的一个非编码区域置于了聚光灯下：这一内含子（基因内区）内的变异与肥胖症和2-型糖尿病的患病风险増加有关。虽然FTO的生物作用已得到深入研究，但仍不清楚这些基因变异体是怎样影响FTO表达和生物功能的。这篇论文显示，这些非编码序列在功能上、在兆碱基距离上是与homeobox基因IRX3相联系的。这一与肥胖相关的间隔似乎属于IRX3而非FTO的调控功能。另外，缺失Irx3的小鼠体重降低，对由饮食诱导的肥胖有抵抗力。综合起来，这些数据表明，IRX3是与人类肥胖症和2-型糖尿病相关的一个重要代谢调控因子。%Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.