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IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk

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...

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Autores principales: Zou, Yaoyu, Lu, Peng, Shi, Juan, Liu, Wen, Yang, Minglan, Zhao, Shaoqian, Chen, Na, Chen, Maopei, Sun, Yingkai, Gao, Aibo, Chen, Qingbo, Zhang, Zhiguo, Ma, Qinyun, Ning, Tinglu, Ying, Xiayang, Jin, Jiabin, Deng, Xiaxing, Shen, Baiyong, Zhang, Yifei, Yuan, Bo, Kauderer, Sophie, Liu, Simin, Hong, Jie, Liu, Ruixin, Ning, Guang, Wang, Weiqing, Gu, Weiqiong, Wang, Jiqiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652024/
https://www.ncbi.nlm.nih.gov/pubmed/28988979
http://dx.doi.org/10.1016/j.ebiom.2017.09.010
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author Zou, Yaoyu
Lu, Peng
Shi, Juan
Liu, Wen
Yang, Minglan
Zhao, Shaoqian
Chen, Na
Chen, Maopei
Sun, Yingkai
Gao, Aibo
Chen, Qingbo
Zhang, Zhiguo
Ma, Qinyun
Ning, Tinglu
Ying, Xiayang
Jin, Jiabin
Deng, Xiaxing
Shen, Baiyong
Zhang, Yifei
Yuan, Bo
Kauderer, Sophie
Liu, Simin
Hong, Jie
Liu, Ruixin
Ning, Guang
Wang, Weiqing
Gu, Weiqiong
Wang, Jiqiu
author_facet Zou, Yaoyu
Lu, Peng
Shi, Juan
Liu, Wen
Yang, Minglan
Zhao, Shaoqian
Chen, Na
Chen, Maopei
Sun, Yingkai
Gao, Aibo
Chen, Qingbo
Zhang, Zhiguo
Ma, Qinyun
Ning, Tinglu
Ying, Xiayang
Jin, Jiabin
Deng, Xiaxing
Shen, Baiyong
Zhang, Yifei
Yuan, Bo
Kauderer, Sophie
Liu, Simin
Hong, Jie
Liu, Ruixin
Ning, Guang
Wang, Weiqing
Gu, Weiqiong
Wang, Jiqiu
author_sort Zou, Yaoyu
collection PubMed
description 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.
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spelling pubmed-56520242017-10-25 IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk Zou, Yaoyu Lu, Peng Shi, Juan Liu, Wen Yang, Minglan Zhao, Shaoqian Chen, Na Chen, Maopei Sun, Yingkai Gao, Aibo Chen, Qingbo Zhang, Zhiguo Ma, Qinyun Ning, Tinglu Ying, Xiayang Jin, Jiabin Deng, Xiaxing Shen, Baiyong Zhang, Yifei Yuan, Bo Kauderer, Sophie Liu, Simin Hong, Jie Liu, Ruixin Ning, Guang Wang, Weiqing Gu, Weiqiong Wang, Jiqiu EBioMedicine Research Paper 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. Elsevier 2017-09-13 /pmc/articles/PMC5652024/ /pubmed/28988979 http://dx.doi.org/10.1016/j.ebiom.2017.09.010 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
Zou, Yaoyu
Lu, Peng
Shi, Juan
Liu, Wen
Yang, Minglan
Zhao, Shaoqian
Chen, Na
Chen, Maopei
Sun, Yingkai
Gao, Aibo
Chen, Qingbo
Zhang, Zhiguo
Ma, Qinyun
Ning, Tinglu
Ying, Xiayang
Jin, Jiabin
Deng, Xiaxing
Shen, Baiyong
Zhang, Yifei
Yuan, Bo
Kauderer, Sophie
Liu, Simin
Hong, Jie
Liu, Ruixin
Ning, Guang
Wang, Weiqing
Gu, Weiqiong
Wang, Jiqiu
IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk
title IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk
title_full IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk
title_fullStr IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk
title_full_unstemmed IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk
title_short IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk
title_sort irx3 promotes the browning of white adipocytes and its rare variants are associated with human obesity risk
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652024/
https://www.ncbi.nlm.nih.gov/pubmed/28988979
http://dx.doi.org/10.1016/j.ebiom.2017.09.010
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