Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites

Abstract

Thyroxine (T4) and 3,5,3'-triiodothyronine (T3) are secreted by the thyroid gland, while T3 is also generated from the peripheral metabolism of T4 by iodothyronine deiodinases types I and II. Several conditions like stress, diseases, and physical exercise can promote changes in local TH metabolism, leading to different target tissue effects that depend on the presence of tissue-specific enzymatic activities. The newly discovered physiological and pharmacological actions of T4 and T3 metabolites, such as 3,5-diiodothyronine (3,5-T2), and 3-iodothyronamine (T1AM) are of great interest. A classical thyroid hormone effect is the ability of T3 to increase oxygen consumption in almost all cell types studied. Approximately 30 years ago, a seminal report has shown that 3,5-T2 increased oxygen consumption more rapidly than T3 in hepatocytes. Other studies demonstrated that exogenous 3,5-T2 administration was able to increase whole body energy expenditure in rodents and humans. In fact, 3,5-T2 treatment prevents diabetic nephropathy, hepatic steatosis induced by high fat diet, insulin resistance, and weight gain during aging in Wistar male rats. The regulation of mitochondria is likely one of the most important actions of T3 and its metabolite 3,5-T2, which was able to restore the thermogenic program of brown adipose tissue (BAT) in hypothyroid rats, just as T3 does, while T1AM administration induced rapid hypothermia. T3 increases heart rate and cardiac contractility, which are hallmark effects of hyperthyroidism involved in cardiac arrhythmia. These deleterious cardiac effects were not observed with the use of 3,5-T2 pharmacological doses, and in contrast T1AM was shown to promote a negative inotropic and chronotropic action at micromolar concentrations in isolated hearts. Furthermore, T1AM has a cardioprotective effect in a model of ischemic/reperfusion injury in isolated hearts, such as occurs with T3 administration. Despite the encouraging possible therapeutic use of TH metabolites, further studies are needed to better understand their peripheral effects, when compared to T3 itself, in order to establish their risk and benefit. On this basis, the main peripheral effects of thyroid hormones and their metabolites in tissues, such as heart, liver, skeletal muscle, and BAT are discussed herein.

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 is found in blood and at even higher concentrations in several tissues. Various groups have demonstrated that 3,5-T2, in addition to its thyromimetic action at the classical T3 receptors at high concentrations, exerts rapid direct effects on mitochondria (6,(16)(17)(18)(19), which might be beneficial in terms of stimulation of oxygen consumption, increased hepatic, and muscular lipid metabolism-all of these effects appear as potentially favorable in global attempts to combat steatosis in liver and other tissues.…”

“…Controversial with respect to this set of observations, several other teams reported that administration of 3,5-T2 in rodent models (rat and mice, regular or high-fat diet, euthyroid or hypothyroid) dose-dependently resulted in significant suppression of the HPT axis as reflected by decreased TSH serum concentrations and/or pituitary beta-TSH transcript levels (6,39,87,94,95). Furthermore, thyromimetic effects typical for high circulating T3 were observed in the heart as analyzed by gene expression and/or morphological alterations suspicious of remodeling and fibrosis.…”

“…A century of thyroxine research has led to the commonly held opinion in the thyroid hormone community that 3,3 ′ ,5,5 ′tetraiodo-L-thyronine (L-Thyroxine, L-T4), which is solely produced by the thyroid gland, serves as a prohormone while T3 (3,3 ′ 5-triiodo-L-thyronine), in part secreted by the thyroid gland, is mainly generated in various extra-thyroidal tissues by either type 1 or type 2 deiodinase (DIO1, DIO2) selenoenzymes (1)(2)(3). T3 exerts the majority of known thyroid hormone (TH) effects at the tissue and cellular level, including hypothalamic and pituitary negative feedback regulation of the hypothalamuspituitary-thyroid-periphery (HPTP) axis (4)(5)(6). Over the last years, some evidence has been presented that T4 also binds to cell membrane-located ανβ3 integrin receptors which exert rapid signaling via various kinase and intracellular pathways, especially in tumor cells and stem cells (7,8).…”

Effect of Soybean, Virgin Coconut and Moringa oleifera Seed Oils on the Propylthiouracil Induced Hypothyroidism in Rats

“…Disorder of thyroid function may produce various subclinical or clinical manifestations (Chaker et al, 2017), such as weight change, sweating, exhaustion, lethargy, cold resistance, voice change, an increase in metabolism of cholesterol, decrease in metabolic rate. Sometimes, there may be swelling of the front part of the neck due to goiter diseases (Louzada and Carvalho, 2018). Hypothyroidism is related to oxidative stress due to excessive free radical growth (Chakrabarti et al, 2016).…”

Effects of Endurance Workouts on Thyroid Hormone Metabolism and Biochemical Markers in Athletes

“…Especially in acute and chronic exercises, thyroid hormone (TSH, T3, T4) release increases. Thyroid hormones, along with exercise, improve the endurance of the organism by affecting protein carbohydrates, fat, metabolism, and adaptation of the organism to physiological and metabolic changes that will occur as a result of exercises (Elliott-Sale et al, 2018;Louzada & Carvalho, 2018). As a consequence of the workout sessions, an important increase was observed in the level of TSH and it was also observed that there was a statistically major difference in T3 and T4 levels.…”