Submitted on February 12, 2007
Accepted on May 16, 2007
3,5-DIIODOTHYRONINE in vivo MAINTAINS EUTHYROIDAL EXPRESSION OF TYPE 2 IODOTHYRONINE DEIODINASE, GROWTH HORMONE, AND THYROID HORMONE RECEPTOR 
1 IN THE KILLIFISH
Carlota García-G1, Lucia N López-Bojorquez2, Jose Nuñez3, Carlos Valverde-R1, and Aurea Orozco2*
1 Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Qro, Queretaro, Mexico; Qro, Queretaro, Mexico
2 Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Qro, Queretaro, Mexico
3 The Whitney Laboratory, University of Florida, St. Augustine, Florida, United States
* To whom correspondence should be addressed. E-mail: aureao{at}servidor.unam.mx.
Until recently, 3,5-T2 has been considered an inactive by-product of T3 deiodination. However, studies from several laboratories have shown that 3,5-T2 has specific, non-genomic effects upon 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 supra-physiological 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 pre-translational effect of 3,5-T2. 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, rT3, 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 up-regulation of D2 and TR
1 and down-regulation of GH that characterize hypothyroidism. Our results demonstrate that 3,5-T2 is indeed bioactive, reversing both hepatic D2 and GH 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-T2 is a bioactive iodothyronine.
