Irx3, encoding Iroquois homeodomain-containing transcription factor, is closely associated with energy homeostasis and obesity-related pathways [1,2]. It is expressed in hypothalamic pro-opiomelanocortin (POMC) neurons and its expression changes impact body adiposity by modulating food intake and energy expenditure. Also, it has been implicated in postnatal hypothalamic neurogenesis, which is important for energy homeostasis [1,2].

In KO/CKO mouse models and other functional studies, several key findings have emerged. For example, overexpression of a dominant-negative form of IRX3 in mouse hypothalamus and adipose tissue promoted energy expenditure by enhancing brown/browning activities [3]. Knockdown of IRX3 impaired the browning program of primary preadipocytes in vitro [3]. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis, as macrophage IRX3 promoted pro-inflammatory cytokine transcription and repressed adipocyte adrenergic signaling, inhibiting lipolysis and thermogenesis [4]. 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 [5].

In conclusion, Irx3 is a crucial regulator in energy homeostasis and adipogenic processes. Studies using KO/CKO mouse models have revealed its role in obesity, metabolic inflammation, and adipocyte function, providing valuable insights into the mechanisms underlying these disease-related processes and suggesting Irx3 as a potential therapeutic target for obesity-related disorders.