3,5-Diiodothyronine (T2) is on a role. A new hormone in search of recognition

•In teleosts, 3,5-T2 regulates gene expression with equivalent potency as that of T3.•In teleosts, 3,5-T2 activates a long TRβ1 containing 9 amino acids more in its LBD.•T2 regulates long TRβ1 expression, suggesting a different signaling pathway than T3.•T2 triggers an outburst of body growth in tilapia by interacting with the long TRβ1.

Thyroid hormone (TH) actions are mediated by triiodothyronine (T3), which acts by binding to the TH receptors (TRs). Since TH exert pleiotropic effects, interest has grown in identifying other possible bioactive thyronines that could explain their diversity of functions. Accordingly, 3,5-diiodothyronine (T2) has been shown to be bioactive. In mammals, T2 regulates mRNA expression of several T3-regulated genes, but doses up to 100-fold greater than those of T3 were required to generate comparable effects. In teleosts, T2 and T3 regulate gene expression in vivo with equivalent potency. Furthermore, in vivo and in vitro studies support the notion that T2 binds to and activates a specific, long TRβ1 isoform that contains a nine amino acid insert at the beginning of the ligand binding domain, whereas T3 can interact also with a different TRβ1 isoform that lacks this insert. Similarly, T2 and T3 differentially regulate long- and short-TRβ1 expression, respectively, strongly suggesting a different signaling pathway for each hormone, at least in the species that express both receptors. In vivo, T2 effectively triggers a burst of body growth in tilapia by interacting with the long TRβ1 isoform, supporting the notion that T2 is physiologically relevant in this species. Current knowledge of T2 effects and action mechanisms lead us to propose that there is an extra level in the thyroid hormone signaling cascade, and that T2 is produced and regulated specifically for this purpose.