3,5-Diiodothyronine: A Novel Thyroid Hormone Metabolite and Potent Modulator of Energy Metabolism

Abstract

Over 30 years of research has demonstrated that 3,5-diiodo-L-thyronine (3,5-T2), an endogenous metabolite of thyroid hormones, exhibits interesting metabolic activities. In rodent models, exogenously administered 3,5-T2 rapidly increases resting metabolic rate and elicits short-term beneficial hypolipidemic effects; however, very few studies have evaluated the effects of endogenous and exogenous T2 in humans. Further analyses on larger cohorts are needed to determine whether 3,5-T2 is a potent additional modulator of energy metabolism. In addition, while several lines of evidence suggest that 3,5-T2 mainly acts through Thyroid hormone receptors (THRs)- independent ways, with mitochondria as a likely cellular target, THRs-mediated actions have also been described. The detailed cellular and molecular mechanisms through which 3,5-T2 elicits a multiplicity of actions remains unknown. Here, we provide an overview of the most recent literature on 3,5-T2 bioactivity with a particular focus on short-term and long-term effects, describing data obtained through in vivo and in vitro approaches in both mammalian and non-mammalian species.

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…The TH metabolite 3,5-T2, possibly formed from its precursor T3 (Figure 1), has recently attracted great interest for several reasons (3,9,15). 3,5-T2 has been considered the main biological active metabolite of T3, formed via further phenolic ring deiodination from T3 (Figure 1).…”

“…Most of these studies were performed in severely hypothyroid, mostly rat models, and 3,5-T2 doses were administered acutely as well as chronically. Unfortunately, no information had been published on 3,5-T2 concentrations reached in the circulation or in those target tissues like liver, where beneficial effects such as antisteatotic activity and increased lipid metabolism were reported (15,17,28,89,90). The first evidence for rapid T3-independent effects of 3,5-T2 on mitochondrial activity and oxygen consumption was provided by Horst et al (16), who observed rapid stimulation of oxygen consumption in isolated perfused livers, removed from hypothyroid rats.…”

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

“…A further problem arises from the degree of purity of commercial preparations of 3,5-T2, used as standards in the measurements; these preparations are, indeed, frequently contaminated with T3 [20,204]. Even with these limitations, 3,5-T2 is now widely considered a bioactive molecule with dose-dependent effects on physiological regulatory functions [20,59,113,191,[204][205][206][207][208][209][210][211].…”

“…Even with these limitations, 3,5-T2 is widely considered a bioactive molecule [20,59,113,191,[204][205][206][207][208][209][210][211]. Thus, in summary, the field is very promising and might offer important advancements in the therapy of obesity and related pathologies.…”

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens—An Insight From Translational Studies

“…As a part of TH metabolism, Dio enzymes are proposed to catalyze the production of physiologically active 3,5-diiodothyronine (3,5-T 2 ) [139]. 3,5-T 2 is present in significant concentrations in human serum [141] and seems to have important implications in the regulation of energy metabolism, with a direct effect on mitochondria as the most likely mechanism [139,[141][142][143] ( Figure 6). So far, serum 3,5-T 2 concentrations have been associated with some pathophysiological states in humans, mainly related to glucose and lipid metabolism [144].…”