Abstract
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A number of the “Past, Present and Future” Delphi Conference participants in the Ancient Theater of Delphi.
The first day of the three-day conference was co-organized by Professor Konstantinos Pantos, cardiologist-pharmacologist (Athens), and was mainly dedicated to thyronamines and their potential physiologic and pathophysiologic role, with particular emphasis being placed on their possible contribution to cardiovascular disease and the regulation of metabolism and body temperature. This session aroused so much interest and discussion that the editors of Thyroid asked Drs. Carolin Hoefig, Riccardo Zucchi, and Josef Köhrle, who were among the presenters in Delphi, to prepare an update on thyronamines, which is being published in this issue of the Journal (1).
3-iodothyronamine (3-T1AM) is an endogenous derivative of thyroxine (T4) generated via decarboxylation, and it can be further metabolized via deiodination to T0AM. It has been postulated that the latter, which has been detected in infinitesimal amounts in human serum, might exert some of the actions of 3-T1AM (1,2). 3-T1AM differs from other biogenic amines by its long half-life, which is thought to be due to its high binding affinity to ApoB100. The administration of exogenous 3-T1AM at micromolar concentrations increases lipid metabolism and exerts a negative inotropic and chronotropic effect in the isolated heart. These nongenomic effects on the heart are possibly mediated through modulation of intracellular calcium homeostasis via membrane receptors, such as trace amine-associated receptors (TAAR), a subclass of the family of G-protein coupled receptors (1,3). In most in vitro and in vivo experiments, high 3-T1AM concentrations have been used, while at nanomolar concentrations, only a few of the observed effects persisted (1,3). In an isolated rat heart model of ischemia-reperfusion injury, treatment with 3-T1AM at 125 nM irreversibly reduced ischemic injury (4). Although the mechanism is not clear, the triggering of signaling cascade(s) by 3-T1AM was proposed (1).
It should be highlighted that 3-T1AM is generated from thyroxine, exerts an agonistic effect with thyroxine on lipid metabolism, and, in the isolated heart, it exhibits partially opposite effects that resemble those seen in hypothyroidism. 3-T1AM opposes thyroxine's primary actions on the heart by protecting the myocardium from the toxicity of high levels of thyroid hormones, as in endogenous and exogenous hyperthyroidism. This suggests the necessity of maintaining a balance between thyroid hormones and 3-T1AM in order to preserve normal cardiac function.
Experimental studies in rodents have demonstrated that 3-T1AM exhibits dose-dependent metabolic effects such as anorexia, as well as decreased energy expenditure and metabolic rate, again showing an action opposite to that of thyroid hormones. A single injection of 3-T1AM to rodents results in a hypometabolic state that resembles hibernation and contrasts with the effects of excess thyroxine (5). This hypometabolic state may be partially explained by a deviation of metabolism from carbohydrate to lipid utilization, which leads to weight reduction and increased lipid mobilization (1). Thyronamines are thought to regulate glucose homeostasis in a manner dependent on dose and mode of administration. Low-dose intracerebroventricular administration of 3-T1AM in rats increased endogenous glucose production, blood glucose, and glucagon, while insulin remained unchanged. Intraperitoneal administration of both 3-T1AM and T0AM failed to reproduce these effects, clearly indicating that a central effect underlies 3-T1AM action (1,6). In addition, intraperitoneal 3-T1AM administration potently stimulates lipolysis and weight loss without affecting food intake (7). 3-T1AM administration appears to increase low-density lipoprotein (LDL) secretion in a neoplastic liver cell line and to promote LDL uptake by LDL receptors in fibroblasts, as well as to reduce cholesterol levels in obese mice when administered at a high dose (1,8). However, similar results could not be reproduced with a low dose of 3-T1AM in mice fed a high-cholesterol diet, which underlines the importance of the dose effect. The molecular mechanisms underlying 3-T1AM effects are currently not known. On the other hand, gene expression analysis in rats chronically treated with T1AM (10 mg/kg twice a day for five days) revealed changes in genes involved in lipolysis and beta-oxidation while inhibiting adipogenesis (9). Thus, by influencing the expression of genes that are implicated in lipoprotein metabolism, 3-T1AM seems to be a lipolytic agent and may therefore have a role in the regulation of cholesterol homeostasis.
It is also noteworthy that 3-T1AM has been shown to protect against stroke injury by inducing hypothermia, an action most that is probably mediated by TAAR and associated with a decreased metabolic rate and oxidative stress (10,11). Thyronamines administered intraperitoneally an hour after middle cerebral artery occlusion lowered mouse body temperature to 31°C from 37°C and significantly reduced brain infarct volume by about 33% at 24 hours (11).
A very interesting recent cross-sectional observational study in intensive care unit (ICU) patients with non-thyroidal illness (NTI) noted that increased deiodinase 3 (D3) and suppressed deiodinase 1 (D1) activity are associated with lower serum 3-T1AM and higher serum 3,5-diiodothyronine (3,5-T2) concentrations (12), which is produced by triiodothyronine (T3) metabolism. The latter effect possibly indicates an increased conversion rate of T4 and/or T3 to 3,5-T2, concomitantly with a decreased 3,5-T2 degradation rate. Non-survivors and ICU patients with diagnosed sepsis had higher 3,5-T2 concentrations compared with other ICU patients, and 3-T1AM but not 3,5-T2 correlated with low T3 (12). The observation that 3-T1AM concentration does not change with severity of illness or even declines with decreasing T3 is compatible with the hypothesis that 3,5-T2 serves as substrate for a decarboxylase yielding 3-T1AM, whose activity is impaired in severe NTI.
Thyronamines, particularly 3-T1AM, are variably effective in biological processes. Despite the fact that many questions remain as to their exact site of generation, mode of action, and dose effects (1), thyronamines represent an intriguing new facet of thyroid hormone metabolism. The outstanding review by Hoefig et al. (1) appearing in this issue of Thyroid excellently summarizes what is known and indicates what research should be carried out to clarify the various roles of these biogenic amines.
It is fervently hoped that the fruitful session on thyronamines, held at the International Conference in the magical surroundings of Delphi, was predictive of important advances in our knowledge of thyroid hormone metabolism and of the pathophysiological implications of these metabolites.