作者：Nature中文網(wǎng)來源：Nature中文網(wǎng)
關(guān)鍵詞： 肥胖 基因 原因
搜尋肥胖的基因原因的工作將FTO基因的一個非編碼區(qū)域置于了聚光燈下：這一內(nèi)含子 (基因內(nèi)區(qū))內(nèi)的變異與肥胖癥和2-型糖尿病的患病風(fēng)險增加有關(guān)。
雖然FTO的生物作用已得到深入研究，但仍不清楚這些基因變異體是怎樣影響FTO表達和生物功能的。這篇論文顯示，這些非編碼序列在功能上、在兆堿基距離上是與homeobox基因IRX3相聯(lián)系的。這一與肥胖相關(guān)的間隔似乎屬于IRX3而非FTO的調(diào)控功能。
另外，缺失Irx3的小鼠體重降低，對由飲食誘導(dǎo)的肥胖有抵抗力。綜合起來，這些數(shù)據(jù)表明，IRX3是與人類肥胖癥和2-型糖尿病相關(guān)的一個重要代謝調(diào)控因子。（
Nature doi:10.1038/nature13138
Obesity-associated variants within FTO form long-range functional connections with IRX3
Scott Smemo， Juan J. Tena， Kyoung-Han Kim， Eric R. Gamazon， Noboru J. Sakabe， Carlos Gómez-Marín， Ivy Aneas， Flavia L. Credidio， Débora R. Sobreira， Nora F. Wasserman， Ju Hee Lee， Vijitha Puviindran， Davis Tam， Michael Shen， Joe Eun Son， Niki Alizadeh Vakili， Hoon-Ki Sung， Silvia Naranjo， Rafael D. Acemel， Miguel Manzanares， Andras Nagy， Nancy J. Cox， Chi-Chung Hui， Jose Luis Gomez-Skarmeta & Marcelo A. Nóbrega
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D)1， 2， 3. 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 phenotypes4， 5， 6. However， no direct connection between the obesity-associated variants and FTO expression or function has been made7， 8， 9. 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.
|
