EBioMedicine (Oct 2017)
IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk
- Yaoyu Zou,
- Peng Lu,
- Juan Shi,
- Wen Liu,
- Minglan Yang,
- Shaoqian Zhao,
- Na Chen,
- Maopei Chen,
- Yingkai Sun,
- Aibo Gao,
- Qingbo Chen,
- Zhiguo Zhang,
- Qinyun Ma,
- Tinglu Ning,
- Xiayang Ying,
- Jiabin Jin,
- Xiaxing Deng,
- Baiyong Shen,
- Yifei Zhang,
- Bo Yuan,
- Sophie Kauderer,
- Simin Liu,
- Jie Hong,
- Ruixin Liu,
- Guang Ning,
- Weiqing Wang,
- Weiqiong Gu,
- Jiqiu Wang
Affiliations
- Yaoyu Zou
- Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Peng Lu
- Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Juan Shi
- 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
- Wen Liu
- 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
- Minglan Yang
- 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
- Shaoqian Zhao
- 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
- Na Chen
- 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
- Maopei Chen
- 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
- Yingkai Sun
- 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
- Aibo Gao
- 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
- Qingbo Chen
- 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
- Zhiguo Zhang
- 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
- Qinyun Ma
- 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
- Tinglu Ning
- Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Xiayang Ying
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, SJTUSM, Shanghai 200025, China
- Jiabin Jin
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, SJTUSM, Shanghai 200025, China
- Xiaxing Deng
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, SJTUSM, Shanghai 200025, China
- Baiyong Shen
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, SJTUSM, Shanghai 200025, China
- Yifei Zhang
- 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
- Bo Yuan
- Department of Burns and Plastic Surgery, Ruijin Hospital, SJTUSM, Shanghai 200025, China
- Sophie Kauderer
- Department of Epidemiology and Center for Global Cardiometabolic Health, School of Public Health, Department of Medicine (Endocrinology), Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Simin Liu
- Department of Epidemiology and Center for Global Cardiometabolic Health, School of Public Health, Department of Medicine (Endocrinology), Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Jie Hong
- 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
- Ruixin Liu
- 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
- Guang Ning
- Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Weiqing Wang
- 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
- Weiqiong Gu
- 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
- Jiqiu Wang
- 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
- DOI
- https://doi.org/10.1016/j.ebiom.2017.09.010
- Journal volume & issue
-
Vol. 24,
no. C
pp. 64 – 75
Abstract
Background: 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. Methods: 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. Results: 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). Conclusions: IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity.
Keywords
