Abstract
BackgroundIRX3 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. MethodsIRX3 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. ResultsIRX3 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). ConclusionsIRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity.
Highlights
Obesity is a complex disease determined by genetic and environmental factors
We showed that IRX3/Irx3 expression was induced in the browning process of white adipose tissue (WAT) in both humans and mice, and its knockdown led to noticeably impaired ability of beige/brown adipocytes program in vitro, possibly by inhibiting Ucp1 promoter transcriptional activity
We further identified the association between rare nonsynonymous IRX3 variants with human obesity risk
Summary
Obesity is a complex disease determined by genetic and environmental factors. The heritability of obesity is as high as 40–70% (Stunkard et al, 1990; Allison et al, 1996), which makes decipherment of obese-related genes extremely important for obesity treatment. A breakthrough in identifying IRX3 as the target of the risk loci in the FTO gene for human obesity (Smemo et al, 2014; Claussnitzer et al, 2015). 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 knockdown remarkably inhibited UCP1 expression in induced mouse and human beige adipocytes, and repressed the uncoupled oxygen consumption rate. Conclusions: IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
