The present study demonstrated the effects of IRX3 on the browning process by the following evidence:﻿ (1) ﻿IRX3/Irx3 reduction by shRNA in vitro dramatically inhibited the browning program and energy expenditure of beige adipocytes, as reflected by the reduced UCP1 levels and oxygen consumption ability, which is a key mechanism for the development of obesity (Wang et al., 2013; Zhang et al., 2014; Lee et al., 2014); ﻿﻿(2) IRX3 significantly activated UCP1 transcriptional activity; (3) two loss-of-function IRX3 mutants identified in human largely abolished this activating effect. Here, IRX3 is linked to obesity due to melanocortin 4 receptor deficiency.