Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals.

Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug.

3,5-Diiodothyronine (T2) is on a role. A new hormone in search of recognition.

Thyroid hormone (TH) actions are mediated by triiodothyronine (T3), which acts by binding to the TH receptors (TRs). Since TH exert pleiotropic effects, interest has grown in identifying other possible bioactive thyronines that could explain their diversity of functions. Accordingly, 3,5-diiodothyronine (T2) has been shown to be bioactive. In mammals, T2 regulates mRNA expression of several T3-regulated genes, but doses up to 100-fold greater than those of T3 were required to generate comparable effects. In teleosts, T2 and T3 regulate gene expression in vivo with equivalent potency. Furthermore, in vivo and in vitro studies support the notion that T2 binds to and activates a specific, long TRß1 isoform that contains a nine amino acid insert at the beginning of the ligand binding domain, whereas T3 can interact also with a different TRß1 isoform that lacks this insert. Similarly, T2 and T3 differentially regulate long- and short-TRß1 expression, respectively, strongly suggesting a different signaling pathway for each hormone, at least in the species that express both receptors. In vivo, T2 effectively triggers a burst of body growth in tilapia by interacting with the long TRß1 isoform, supporting the notion that T2 is physiologically relevant in this species. Current knowledge of T2 effects and action mechanisms lead us to propose that there is an extra level in the thyroid hormone signaling cascade, and that T2 is produced and regulated specifically for this purpose.

Hippocampal gene expression of deiodinases 2 and 3 and effects of 3,5-diiodo-L-thyronine T2 in mouse depression paradigms.

Central thyroid hormone signaling is important in brain function/dysfunction, including affective disorders and depression. In contrast to 3,3',5-triiodo-L-thyronine (T3), the role of 3,5-diiodo-L-thyronine (T2), which until recently was considered an inactive metabolite of T3, has not been studied in these pathologies. However, both T3 and T2 stimulate mitochondrial respiration, a factor counteracting the pathogenesis of depressive disorder, but the cellular origins in the CNS, mechanisms, and kinetics of the cellular action for these two hormones are distinct and independent of each other. Here, Illumina and RT PCR assays showed that hippocampal gene expression of deiodinases 2 and 3, enzymes involved in thyroid hormone regulation, is increased in resilience to stress-induced depressive syndrome and after antidepressant treatment in mice that might suggest elevated T2 and T3 turnover in these phenotypes. In a separate experiment, bolus administration of T2 at the doses 750 and 1,500 mcg/kg but not 250 mcg/kg in naive mice reduced immobility in a two-day tail suspension test in various settings without changing locomotion or anxiety. This demonstrates an antidepressant-like effect of T2 that could be exploited clinically. In a wider context, the current study suggests important central functions of T2, whose biological role only lately is becoming to be elucidated.