From an evolutionary perspective, deiodinases may be considered pivotal players in the emergence and functional diversification of both thyroidal systems (TS) and their iodinated messengers. To better understand the evolutionary pathway and the concomitant functional diversification of vertebrate deiodinases, in the present review we summarized the highlights of the available information regarding this ubiquitous enzymatic component that represents the final, common physiological link of TS. The information reviewed here suggests that deiodination of tyrosine metabolites is an ancient feature of all chordates studied to date and consequently, that it precedes the integration of the TS that characterize vertebrates. Phylogenetic analysis presented here points to D1 as the oldest vertebrate deiodinase and to D2 as the most recent deiodinase gene, a hypothesis that agrees with the notion that D2 is the most specialized and finely regulated member of the family and plays a key role in vertebrate neurogenesis. Thus, deiodinases seem to be major participants in the evolution and functional expansion of the complex regulatory network of TS found in vertebrates.

Until recently,3, has been considered an inactive by-product of triiodothyronine (T3) deiodination. However, studies from several laboratories have shown that 3,5-T2 has specific, nongenomic effects on mitochondrial oxidative capacity and respiration rate that are distinct from those due to T3. Nevertheless, little is known about the putative genomic effects of 3,5-T2. We have previously shown that hyperthyroidism induced by supraphysiological doses of 3,5-T2 inhibits hepatic iodothyronine deiodinase type 2 (D2) activity and lowers mRNA levels in the killifish in the same manner as T3 and T4, suggesting a pretranslational effect of 3,5-T2 (Garcia-G C, Jeziorski MC, Valverde-R C, Orozco A. Gen Comp Endocrinol 135: 201-209, 2004). The question remains as to whether 3,5-T2 would have effects under conditions similar to those that are physiological for T3. To this end, intact killifish were rendered hypothyroid by administering methimazole. Groups of hypothyroid animals simultaneously received 30 nM of either T3, reverse T3, or 3,5-T2. Under these conditions, we expected that, if it were bioactive, 3,5-T2 would mimic T3 and thus reverse the compensatory upregulation of D2 and tyroid receptor ␤1 and downregulation of growth hormone that characterize hypothyroidism. Our results demonstrate that 3,5-T2 is indeed bioactive, reversing both hepatic D2 and growth hormone responses during a hypothyroidal state. Furthermore, we observed that 3,5-T2 and T3 recruit two distinct populations of transcription factors to typical palindromic and DR4 thyroid hormone response elements. Taken together, these results add further evidence to support the notion that 3,5-T 2 is a bioactive iodothyronine. deiodinase type 2; thyroid hormone receptor ␤1; thyroid hormone response element; killifish IODOTHYRONINES OR THYROID hormones (TH) are essential in regulating energy expenditure and development. Triiodothyronine (T 3 ) is the bioactive TH, which modulates gene expression in virtually every vertebrate tissue through ligand-dependent transcription factors, the TH receptors (TR). Sequential deiodination of thyroxine (T 4 ) generates T 3 as well as other iodothyronines that have been considered inactive by-products, but, recently, interest has grown in identifying bioactive iodothyronines in addition to T 4 and T 3 . Studies from several laboratories have suggested that 3,5-diiodothyronine (3,5-T 2 ), a putative product of the deiodination pathway involved in T 3 metabolism, could be a peripheral mediator of some effects of TH on mitochondrial oxidative capacity and respiration rate. To date, results in mammals suggest that 3,5-T 2 has specific actions on oxygen consumption that are distinct from those of T 3 : they are not attenuated by inhibition of protein synthesis and are more rapid than those due to T 3 (for review, see Ref. 12). Genomic effects of 3,5-T 2 have been analyzed in only a few classic iodothyronine-dependent genes, such as thyroid stimulating hormone (TSH), thyroid receptor ␤2 (TR␤2), iodothyronine deiodinase type 1 (D1)...

SUMMARY The physiological role played by thyroid hormones (TH) in hydro-osmotic homeostasis in fish remains a controversial issue. Previous studies have shown that in Fundulus heteroclitus (killifish) hypo-osmotic stress increases liver iodothyronine deiodinase type 2 (D2) mRNA and D2 activity. In this study we identified two conserved osmotic response element (ORE) motifs in the promoter region of the killifish D2 gene (FhDio2) and examined their possible role in the transcriptional regulation of FhDio2during hypo-osmotic stress. As assessed by the electrophoretic mobility shift assay, results from in vivo and in vitro experiments demonstrate that exposure to an abrupt hyposmotic challenge triggers in the liver of killifish a strong nuclear recruitment of a putative osmotic response element binding protein (OREBP). This protein–DNA binding is time-dependent, attains a maximum within 2–8 h after the osmotic stress,and is followed by a significant increase in D2 activity. Furthermore,protein–DNA binding and the subsequent elevation in enzyme activity were blocked by the tyrosine kinase inhibitor genistein. Thus, during hypo-osmotic stress, a putative OREBP kinase-activated pathway stimulates FhDio2transcription and enzymatic activity. These data and the fact that D2 is the major enzyme providing local intracellular T3 suggest that TH plays a direct role in osmoregulation in fish, possibly by participating in hepatic ammonia metabolism. This study provides important insight into the physiological role of TH in hydro-osmotic homeostasis in fish.

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