Irx3, encoding Iroquois homeodomain-containing transcription factor, has emerged as a crucial regulator in multiple biological processes. It is significantly associated with energy homeostasis-related pathways, with its dysregulation linked to obesity. Genome-wide association studies have shown its connection with SNPs in the FTO gene, suggesting its importance in understanding the genetic basis of obesity [1,3].

In KO mouse models, myeloid-specific deletion of Irx3 protected against diet-induced obesity and metabolic diseases by increasing adaptive thermogenesis. Mechanistically, macrophage Irx3 promoted pro-inflammatory cytokine transcription, repressed adipocyte adrenergic signaling, and thus inhibited lipolysis and thermogenesis [2]. Stable knockout of Irx3 in ME3 mouse preadipocytes capable of beiging impaired proliferation, ROS generation, mitochondrial respiration, and adipogenic differentiation, suggesting Irx3 is essential for preadipocyte identity and differentiation capacity [4]. Mice with deletion of Irx3 in specific cells exhibited lower food intake with enhanced hypothalamic leptin response, indicating Irx3's role in regulating hypothalamic postnatal neurogenesis and leptin response [5].

In conclusion, Irx3 is vital for maintaining normal physiological functions related to energy metabolism, adipocyte differentiation, and hypothalamic regulation. Mouse KO models have been instrumental in revealing its role in diet-induced obesity, adipogenic differentiation, and hypothalamic-related processes, providing valuable insights into potential therapeutic targets for obesity and related metabolic diseases.

References:

1. de Araújo, Thiago Matos, Velloso, Licio A. 2020. Hypothalamic IRX3: A New Player in the Development of Obesity. In Trends in endocrinology and metabolism: TEM, 31, 368-377. doi:10.1016/j.tem.2020.01.002. https://pubmed.ncbi.nlm.nih.gov/32035736/

2. Yao, Jingfei, Wu, Dongmei, Zhang, Chunyan, Wang, Zihao, Qiu, Yifu. 2021. Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation. In Nature immunology, 22, 1268-1279. doi:10.1038/s41590-021-01023-y. https://pubmed.ncbi.nlm.nih.gov/34556885/

3. Littleton, Sheridan H, Berkowitz, Robert I, Grant, Struan F A. 2020. Genetic Determinants of Childhood Obesity. In Molecular diagnosis & therapy, 24, 653-663. doi:10.1007/s40291-020-00496-1. https://pubmed.ncbi.nlm.nih.gov/33006084/

4. Bjune, Jan-Inge, Dyer, Laurence, Røsland, Gro V, Dankel, Simon N, Mellgren, Gunnar. 2019. The homeobox factor Irx3 maintains adipogenic identity. In Metabolism: clinical and experimental, 103, 154014. doi:10.1016/j.metabol.2019.154014. https://pubmed.ncbi.nlm.nih.gov/31751577/

5. Son, Joe Eun, Dou, Zhengchao, Kim, Kyoung-Han, Huang, Xi, Hui, Chi-Chung. 2021. Irx3 and Irx5 in Ins2-Cre+ cells regulate hypothalamic postnatal neurogenesis and leptin response. In Nature metabolism, 3, 701-713. doi:10.1038/s42255-021-00382-y. https://pubmed.ncbi.nlm.nih.gov/33859429/