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

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.

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

“…IL11, IL20RA, IL27RA) could be linked to less thermogenic DN adipocytes and thereby to obesity and inflammation [44]. Finally, IRX3, which was already described as a negative [19] and positive [45] regulator of the development of thermogenic adipocytes, was also among the genes kept lowly expressed in DN and FTO T/T adipocytes but became higher expressed in the adipocytes with the obesityrisk genotype.…”

“…A super-enhancer, which is located on an obesity-risk associated locus of the intronic region of the FTO gene, was linked to the regulation of browning in subcutaneous fat [19,45,59,60] by determining the level of IRX3 and IRX5. The role of IRX3 and 5 in this signaling pathway is still controversial [19,45,59]. In our study, IRX3 was significantly higher expressed in samples with FTO obesity-risk alleles and support its suppressive role in thermogenesis.…”

Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development

“…Claussnitzer et al proposed a mechanism by which obesity risk alleles of rs1421085 in human mesenchymal adipocyte progenitors increase expression of IRX3/5, resulting in decreased thermogenic potential of new adipocytes. However, a follow-up study presented in vivo and in vitro evidence that Irx3 positively regulates thermogenesis (62). The relevance of these mechanisms in humans is unclear, as the effects of the obesity-risk alleles in the first intron of FTO have been consistently reported to convey effects on food intake and not energy expenditure (6,(63)(64)(65)(66)(67)(68)(69)(70)(71).…”

Family-based quantitative trait meta-analysis implicates rare noncoding variants inDENND1Ain pathogenesis of polycystic ovary syndrome

“…As GWAS were 60 designed to assess common allelic variants, usually with minor allele frequencies (MAF) ≥2-61 5%, it has been proposed that less frequently occurring variants with greater effect sizes 2 account for the observed deficit in heritability 10 . Next generation sequencing approaches have 63 identified rare variants that contribute to complex disease pathogenesis [11][12][13][14][15][16] .…”