Although a previous report shows an inhibitory effect of NFAT5 on beiging of WAT to promote obesity [50], our present findings demonstrate that NFAT5 acts downstream of Epac1 to positively regulate UCP1 transcription during beiging in vivo and beige adipogenesis in vitro, suggesting that NFAT5 might have opposite effects upon differential upstream regulations. This evidence concerns the gene UCP1 and obesity due to melanocortin 4 receptor deficiency.