As obesity-risk variants of FTO affect the expression levels of both IRX3 and IRX5 (Claussnitzer et al., 2015; Laber et al., 2021; Sobreira et al., 2021), Irx3/5dHet mice serve as a preclinical model mimicking lower IRX3 and IRX5 expression levels in humans. Here, IRX3 is linked to obesity due to melanocortin 4 receptor deficiency.