Until recently, 3,5-diiodothyronine (3,5-T₂) has been considered an inactive by-product of triiodothyronine (T₃) deiodination. However, studies from several laboratories have shown that 3,5-T₂has 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-T₂inhibits hepatic iodothyronine deiodinase type 2 (D2) activity and lowers mRNA levels in the killifish in the same manner as T₃and 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-T₂would 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-T₂would mimic T₃and thus reverse the compensatory upregulation of D2 and tyroid receptor β1 and downregulation of growth hormone that characterize hypothyroidism. Our results demonstrate that 3,5-T₂is indeed bioactive, reversing both hepatic D2 and growth hormone responses during a hypothyroidal state. Furthermore, we observed that 3,5-T₂and T₃recruit 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-T₂is a bioactive iodothyronine.

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