Mice with one thyroid hormone receptor (TR) α-1 allele encoding a dominant negative mutant receptor (TRα1^PV/+) have persistently elevated serum T₃ levels (1.9-fold above normal). They also have markedly increased hepatic type 1 iodothyronine deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T₃-responsive genes, such as Spot14 and mitochondrial α-glycerol phosphate dehydrogenase (α-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TRα1^+/+). To determine the cause of the disproportionate elevation of D1, TRα1^+/+ and TRα1^PV/+ mice were rendered hypothyroid and then treated with T₃. Hypothyroidism decreased hepatic D1, Spot14, and α-GPD mRNA to similar levels in TRα1^+/+ and TRα1^PV/+ mice, whereas T₃ administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and α-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 iodothyronine deiodinase activity was 3 times greater in the TRα1^PV/+ mice, and these mice had no T₃-dependent induction of type 3 iodothyronine deiodinase. Thus, the marked responsiveness of hepatic D1 to T₃ relative to other genes, such as Spot14 and α-GPD, explains the relatively large effect of the modest increase in serum T₃ in the TRα1^PV/+ mice, and TRα plays a key role in T₃-dependent positive and negative regulation of the deiodinases in the cerebral cortex.