Several liganded nuclear receptors have alternative ligands acting in a tissue-specific fashion and playing important biological roles. We present evidence that 3,5-diiodothyronine (T2), a naturally occurring iodothyronine that results from T3 outer-ring deiodination, is an alternative ligand for thyroid hormone receptor β1 (TRβ1). In tilapia, 2 TRβ isoforms differing by 9 amino acids in the ligand-binding domain were cloned. Binding and transactivation studies showed that T2 activates the human and the long tilapia TRβ1 isoform, but not the short one. A chimeric human TRβ1 (hTRβ1) that contained the 9–amino-acid insert showed no response to T2, suggesting that the conformation of the hTRβ1 naturally allows T2 binding and that other regions of the receptor are implicated in TR activation by T2. Indeed, further analysis showed that the N terminus is essential for T2-mediated transactivation but not for that by T3 in the long and hTRβ1, suggesting a functional interaction between the N-terminal domain and the insertion in the ligand-binding domain. To establish the functional relevance of T2-mediated TRβ1 binding and activation, mRNA expression and its regulation by T2 and T3 was evaluated for both isoforms. Our data show that long TRβ1expression is 106-fold higher than that of the short isoform, and T3 and T2 differentially regulate the expression of these 2 TRβ1 isoforms in vivo. Taken together, our results prompted a reevaluation of the role and mechanism of action of thyroid hormone metabolites previously believed to be inactive. More generally, we propose that classical liganded receptors are only partially locked to very specific ligands and that alternative ligands may play a role in the tissue-specific action of receptors.

Recent studies in our laboratory have shown that in some teleosts, 3,5-di-iodothyronine (T₂ or 3,5-T₂) is as bioactive as 3,5,3′-tri-iodothyronine (T₃) and that its effects are in part mediated by a TRβ1 (THRB) isoform that contains a 9-amino acid insert in its ligand-binding domain (long TRβ1 (L-TRβ1)), whereas T₃ binds preferentially to a short TRβ1 (S-TRβ1) isoform that lacks this insert. To further understand the functional relevance of T₂ bioactivity and its mechanism of action, we used in vivo and ex vivo (organotypic liver cultures) approaches and analyzed whether T₃ and T₂ differentially regulate the S-TRβ1 and L-TRβ1s during a physiological demand such as growth. In vivo, T₃ and T₂ treatment induced body weight gain in tilapia. The expression of L-TRβ1 and S-TRβ1 was specifically regulated by T₂ and T₃ respectively both in vivo and ex vivo. The TR antagonist 1–850 effectively blocked thyroid hormone-dependent gene expression; however, T₃ or T₂ reversed 1–850 effects only on S-TRβ1 or L-TRβ1 expression, respectively. Together, our results support the notion that both T₃ and T₂ participate in the growth process; however, their effects are mediated by different, specific TRβ1 isoforms.

Continuous illumination has been known to exert positive effects by stimulating growth and delaying unwanted maturation in seasonal-temperate farmed fish species like salmonids. However, in tropical fish like Nile tilapia ( Oreochromis niloticus ), some studies exist showing inconsistent results and even fewer data is available regarding the effects of light intensity. To clarify some of the inconsistent results in literature and evaluate the effect of different light intensity levels on growth and sexual maturation in Nile tilapia ( [...] ABSTRACT Continuous illumination has been known to exert positive effects by stimulating growth and delaying unwanted maturation in seasonal-temperate farmed fish species like salmonids. However, in tropical fish like Nile tilapia ( Oreochromis niloticus ), some studies exist showing inconsistent results and even fewer data is available regarding the effects of light intensity. To clarify some of the inconsistent results in literature and evaluate the effect of different light intensity levels on growth and sexual maturation in Nile tilapia (