Regulation of Dio2 gene expression by thyroid hormones in normal and type 1 deiodinase-deficient C3H mice

The C3H/HeJ mouse presents an inherited type 1 deiodinase (D1) deficiency that results in elevated serum thyroxine (T(4)), whereas TSH and tri-iodothyronine (T(3)) concentrations are normal when compared with those in the C57BL/6J strain. Here, we evaluated the expression of the type 2 (D2), the other T(4)-activating enzyme, in C3H mice. A comparative analysis revealed that D2 mRNA levels in C3H are similar to those in C57 animals. The D2 activity in C3H pituitary and brain are reduced when compared with those in the C57 strain (3.75 +/- 1.08 vs 5.78 +/- 0.33 and 0.17 +/- 0.05 vs 0.26 +/- 0.07 fmol/min per mg protein respectively). However, no differences on D2 activity levels were observed in the brown adipose tissue (BAT) between both strains (0.34 +/- 0.06 vs 0.36 +/- 0.09 fmol/min per mg protein). Experiments using different T(4) doses showed that higher levels of serum T(4) than those of the C3H mouse are required to downregulate D2 activity in this tissue. T(3) administration to euthyroid mice resulted in a two- to four-fold increase on D2 activity in BAT and brain of both strains, despite a marked decrease in BAT D2 transcripts and no changes in brain D2 mRNA levels. The increase in D2 activity was preceded by a decrease in serum T(4) levels, which appears to reduce D2 degradation. Indeed, administration of T(3) plus T(4) abolished the T(3)-induced D2 upregulation. In conclusion, our results demonstrated that D2 activity is mainly regulated at posttranslational level in a tissue-specific manner. These observations further characterize and provide insights into the complex and dual regulatory role of the iodothyronines in D2 regulation.