Deiodinases modify the biological activity of thyroid hormone (TH) molecules, i.e. they may activate thyroxine (T4) to 3,5,3’-tri-iodothyronine (T3), or inactivate T3 to 3,3’-diiodo-L-thyronine (T2) or T4 to reverse tri-iodothyronine (rT3). Although evidence of deiodination of T4 to T3 was available since the 1950s, objective evidence of TH metabolism was not established until the 1970s. The modern paradigm considers that the deiodinases not only play a role in the homeostasis of circulating T3, but they also provide dynamic control of TH signaling: cells that express the activating type 2 deiodinase (D2) have enhanced TH signaling due to intracellular build-up of T3; the opposite is seen in cells that express type 3 deiodinase (D3), the inactivating deiodinase. D2 and D3 are expressed in metabolically relevant tissues such as brown adipose tissue, skeletal muscle and liver, and their roles have been investigated using cell, animal, and human models. During development, D2 and D3 expression customize for each tissue/organ the timing and intensity of TH signaling. In adult cells, D2 is induced by cyclic adenosine monophosphate (cAMP) and its expression is invariably associated with enhanced T3 signaling, expression of PGC1 and accelerated energy expenditure. In contrast, D3 expression is induced by hypoxia-inducible factor 1- α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling on a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.

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Adaptive thermogenesis in small mammals and infants takes place in the brown adipose tissue (BAT). Heat is produced via UCP1-mediated uncoupling between oxidation of energy substrates and ATP synthesis. Thyroid hormone signaling plays a role in this process. The deiodinases activate T4 to T3 (D2) or inactivate T4 and T3 to rT3 and T2 (D3), respectively. Using a mouse model with selective inactivation of Dio3 in BAT (flox-Dio3 x UCP1-cre = BAT-D3KO), we now show that knocking out D3 resulted in premature exposure of developing brown adipocytes (E16.5-18.5) to T3 signaling, leading to an earlier expression of key BAT genes, i.e. Cidea, Cox8b, Dio2, Ucp1, and Pgc1α. Adult BAT-D3KO mice exhibited increased expression of 1591 genes as assessed by RNA-seq, including 19 gene sets related to mitochondria, 8 related to fat, and 8 related to glucose homeostasis. The expression of 243 genes was changed by >1.5-fold, 36 of which play a role in metabolic/thermogenic processes. The BAT-D3KO mice weigh less and exhibit smaller white adipocyte area, but maintain normal energy expenditure at room temperature (22°C) and in the cold (4°C). They also defend their core temperature more effecttively and did not lose as much body weight when exposed to cold. We conclude that the coordinated actions of Dio3 in the embryonic BAT define the timing and intensity of T3 signaling during brown adipogenesis. Enhanced T3 signaling during BAT embryogenesis (Dio3 inactivation) results in selective life-long modifications in BAT transcriptome.