FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.
FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.
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DOI：
10.1056/nejmoa1502214
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发表时间：
2015-09-03
期刊：
影响因子：
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通讯作者：
Kellis M
中科院分区：
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作者：
Claussnitzer M;Dankel SN;Kim KH;Quon G;Meuleman W;Haugen C;Glunk V;Sousa IS;Beaudry JL;Puviindran V;Abdennur NA;Liu J;Svensson PA;Hsu YH;Drucker DJ;Mellgren G;Hui CC;Hauner H;Kellis M
全基因组关联研究可用于确定与疾病相关的基因组区域，但对数据的解释具有挑战性。FTO区域与肥胖有着最强烈的遗传联系，然而这种联系的机制基础仍然难以捉摸。我们检查了表观基因组数据、等位基因活性、基序保护、调节因子表达和基因共表达模式，目的是剖析FTO区域与肥胖之间关联的调控回路和机制基础。我们在患者和小鼠样本中使用定向扰动，并在患者样本中使用内源性CRISPR-Cas9基因组编辑，验证了我们的预测。我们的数据表明，与肥胖相关的FTO等位基因以组织自主的方式抑制脂肪细胞前体细胞中的线粒体产热。rs1421085 T-to-C单核苷酸变体破坏了ARID5B抑制因子的保守基序，从而导致一种有效的前脂肪细胞增强子的抑制，以及在脂肪细胞早期分化过程中IRX3和IRX5表达的翻倍。这导致细胞自主发育转变，从能量耗散的米色（白垩）脂肪细胞到能量储存的白色脂肪细胞，线粒体产热减少5倍，脂质储存增加。抑制小鼠脂肪组织中的Irx3可减轻体重，增加能量消耗，但不会改变身体活动或食欲。在具有风险等位基因的参与者的原代脂肪细胞中，IRX3或IRX5的敲低恢复了产热作用，将其增加了7倍，而在非风险等位基因携带者的脂肪细胞中，这些基因的过表达具有相反的效果。通过CRISPR-Cas9编辑风险等位基因rs1421085修复ARID5B基序，恢复了IRX3和IRX5的抑制，激活了褐变表达程序，恢复了产热，使其增加了7倍。我们的研究结果指出了一条涉及ARID5B、rs1421085、IRX3和IRX5的脂肪细胞产热调节通路，当这些通路被操纵时，具有明显的促肥胖和抗肥胖作用。（由德国环境健康研究中心等资助。）
Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR–Cas9 genome editing in samples from patients. Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR–Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.)