Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Endocrinology and Metabolism, National Key Laboratory for Medical Genomes, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China; Shanghai Ji Ai Genetics & IVF Institute, Obstetrics & Gynecology Hospital, Fudan University, Shanghai 200011, China.
Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
EBioMedicine. 2017 Oct;24:64-75. doi: 10.1016/j.ebiom.2017.09.010. Epub 2017 Sep 13.
IRX3 was recently reported as the effector of the FTO variants. We aimed to test IRX3's roles in the browning program and to evaluate the association between the genetic variants in IRX3 and human obesity.
IRX3 expression was examined in beige adipocytes in human and mouse models, and further validated in induced beige adipocytes. The browning capacity of primary preadipocytes was assessed with IRX3 knockdown. Luciferase reporter analysis and ChIP assay were applied to investigate IRX3's effects on UCP1 transcriptional activity. Moreover, genetic analysis of IRX3 was performed in 861 young obese subjects and 916 controls.
IRX3 expression was induced in the browning process and was positively correlated with the browning markers. IRX3 knockdown remarkably inhibited UCP1 expression in induced mouse and human beige adipocytes, and also repressed the uncoupled oxygen consumption rate. Further, IRX3 directly bound to UCP1 promoter and increased its transcriptional activity. Moreover, 17 rare heterozygous missense/frameshift IRX3 variants were identified, with a significant enrichment in obese subjects (P=0.038, OR=2.27; 95% CI, 1.02-5.05).
IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity.
IRX3 最近被报道为 FTO 变异体的效应物。我们旨在研究 IRX3 在棕色化程序中的作用，并评估 IRX3 基因变异与人类肥胖之间的关联。
在人源和鼠源的米色脂肪细胞中检测 IRX3 的表达情况，并在诱导的米色脂肪细胞中进一步验证。利用 IRX3 敲低评估原代前体脂肪细胞的棕色化能力。应用荧光素酶报告分析和 ChIP 实验来研究 IRX3 对 UCP1 转录活性的影响。此外，对 861 名年轻肥胖受试者和 916 名对照进行了 IRX3 的遗传分析。
IRX3 的表达在棕色化过程中被诱导，且与棕色化标志物呈正相关。IRX3 敲低显著抑制诱导的鼠源和人源米色脂肪细胞中 UCP1 的表达，并抑制解偶联耗氧量。此外，IRX3 直接结合 UCP1 启动子并增加其转录活性。此外，还鉴定出 17 种罕见的杂合错义/移码 IRX3 变体，在肥胖受试者中显著富集（P=0.038，OR=2.27；95%CI，1.02-5.05）。
IRX3 缺陷通过调节 UCP1 转录活性部分抑制白色脂肪细胞的棕色化程序。IRX3 的罕见变体与人类肥胖有关。
