Deiodinases and the Metabolic Code for Thyroid Hormone Action

Abstract

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.

Sex Dimorphic Responses of the Hypothalamus-Pituitary-Thyroid Axis to Energy Demands and Stress

“…TH tissue-concentrations are regulated by the activity of deiodinases (Dio1, 2 and 3) in a tissue-specific manner ( 17 , 18 ). Dio1 in thyroid, liver, and kidney, regulates the systemic concentration of T3; however, because of its preference for deiodination of T4 inner ring, it produces more of the inactive metabolite 3,3’,5’-triiodothyronine or reverse T3 (rT3) than T3.…”

“…Dio1 in thyroid, liver, and kidney, regulates the systemic concentration of T3; however, because of its preference for deiodination of T4 inner ring, it produces more of the inactive metabolite 3,3’,5’-triiodothyronine or reverse T3 (rT3) than T3. In hypothalamus, pituitary and target tissues like skeletal muscle, white adipose tissue (WAT) and brown adipose tissue (BAT), Dio2 is responsible of T4 conversion to T3; Dio3 converts T4 to rT3, and T3 to 3,5-diiodothyronine ( 17 , 18 ). Excretion of TH is catalyzed by UDP-glucuronyltransferases (UGT) located in the liver ( 19 ); rodents contain additional conjugating enzymes, sulfotransferases (SULT) ( 19 , 20 ).…”

Maternal LiCl exposure disrupts thyroid–cerebral axis in neonatal albino rats

“…Thus, LiCl disrupts the neonatal cerebral DII and DIII that are essential for determining the available T3 during the development. The coordination between these enzymes can adjust T3 signalling in a mosaic way (in a time-and tissue-specific mode), influencing metabolic pathways in normal and abnormal states (Russo et al, 2021).…”

Bioenergetic Aspects of Mitochondrial Actions of Thyroid Hormones

“…However, some evidences suggest that other iodothyronines, such as T4 itself, and reverse T3 (rT3) as well as, other TH metabolites, such as 3-iodothyronamine (T1AM) and 3,5-diiodo-L-thyronine (T2) may possess significant biological activity [16][17][18][19]. The biological activity of T3 is largely determined by its intracellular concentration, which is dependent on its transport across the cell membrane (through transporters that belong to the monocarboxylate transporter 8, organic-anion-transporting polypeptide 1, and the L-type amino acid transporter families), and the presence of iodothyronine deiodinases (DIOs) and other enzymes such as decarboxylase and deaminase [16,[20][21][22][23]. DIO1 and DIO2, the so-called activating DIOs, convert intracellular T4 to T3, while DIO3, the so-called inactivating DIO, converts T3 to rT3.…”