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.

No abstract

Objective: To determine the relationship of the gain-of-function variant A750T in leucine-rich repeat containing G protein-coupled receptor 4 (LGR4) with central obesity and related metabolic phenotypes. Methods: The LGR4 A750T (c.2248 G > A) variant was detected by Sanger sequencing in a discovery young population and a validation community-based population with obesity from eastern China. Fat indices determined by anthropometry and computed tomography scans and clinical biochemical measurements were collected for association analysis. Results: LGR4 A750T was significantly correlated with waist circumference (P 5 0.030) and waist-toheight ratio (P < 0.001) in the young cohort (N 5 594) and with waist-to-hip ratio (P 5 0.013) in the community population (N 5 1067). Combined analysis showed a significant correlation of the variant with waist circumference (P < 0.001) and waist-to-hip ratio (P 5 0.021). Moreover, the variant had a remarkable correlation with abdominal visceral fat area (P 5 0.004) and was associated with 2-h plasma insulin (P 5 0.009) and the Matsuda index (P 5 0.027) after an oral glucose tolerance test in young subjects with obesity. Conclusions: The LGR4 A750T variant may contribute to central obesity characterized by abdominal visceral fat accumulation.