Irx3, encoding Iroquois homeodomain-containing transcription factor, is significantly associated with energy homeostasis and obesity-related pathways. It is regulated by long-range enhancers from the intronic regions of the FTO gene, and its expression in hypothalamic pro-opiomelanocortin (POMC) neurons can influence body adiposity by modulating food intake and energy expenditure [1].

In KO/CKO mouse models, myeloid-specific deletion of Irx3 protected mice 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]. Also, stable knockout of Irx3 in ME3 mouse preadipocytes impaired their proliferation, ROS generation, and mitochondrial respiration, and led to a loss of preadipocyte identity and a gain of chondrocyte-like identity during early differentiation [3].

In conclusion, Irx3 is crucial in maintaining adipogenic identity and regulating energy homeostasis. Mouse KO/CKO models have revealed its role in promoting diet-induced obesity and metabolic inflammation, as well as its importance in preadipocyte differentiation, providing insights into obesity-related disease mechanisms.