Endocrine, Metabolic and Pharmacological Effects of Thyronamines (TAM), Thyroacetic Acids (TA) and Thyroid Hormone Metabolites (THM) – Evidence from in vitro, Cellular, Experimental Animal and Human Studies

Abstract

Thyroid hormone metabolites (THM) with few or no iodine substituents such as 3,5-T2, the thyronamines 3-T1AM and T0AM, and their oxidation products, the thyroacetic acids (TA) formed by monoamine oxidases, have recently attracted major interest due to their metabolic actions which are in part distinct from those of the classical thyromimetic hormone T3, the major ligand of T3 receptors. This review compiles and discusses in vitro effects of 3,5-T2, TAM and TA reported for thyrocytes, pancreatic islets and hepatocytes as well as findings from in vivo studies in mouse models after single or repeated administration of pharmacological doses of these agents. Comparison of the 3,5-T2 effects on the transcriptome with not yet published proteome data in livers of obese mice on high fat diet indicate a distinct anti-steatotic effect of this THM. Furthermore, uptake, metabolism, and cellular actions via various receptors such as trace amine-associated receptors (TAAR), alpha-adrenergic, GPCR and T3 receptors are discussed. Studies on postulated pathways of biosynthesis of 3-T1AM, its effects on the HPT-axis and thyroid gland as well as insulin secretion are reviewed. 3-T1AM also acts on hepatocytes and interferes with TRPM8-dependent signaling in human cell lines related to the eye compartment. Human studies are presented which address potential biosynthesis routes of 3,5-T2 and 3-T1AM from THM precursors, especially T3. The current state of diagnostic analytics of these minor THM in human blood is portrayed comparing and critically discussing the still divergent findings based on classical immunoassay and recently developed liquid-chromatography/mass- spectrometry methods, which allow quantification of the thyronome spectrum from one single small volume serum sample. The clinical perspectives of use and potential abuse of these biologically active THM is addressed.

Abnormal Cardiac Repolarization in Thyroid Diseases: Results of an Observational Study

“…Limitations of our approach are in the comparably small sample size and in the fact that subjects were recruited based on routine investigations, so that we were unable to determine non-classical thyroid hormones including 3,5-diiodothyronine (3,5-T2), thyronamines and iodothyroacetates, which may have a strong impact on cardiovascular physiology ( 42 – 44 ). Furthermore, our ECGs were not obtained digitally so that automatic measurements with a higher accuracy than the manual method could not be performed.…”

Seven Years of Active Thyroid Hormone Research in Germany: Thyroid Hormone Action beyond Classical Concepts

“…Sophisticated TH research requires the development of methods for a comprehensive determination of TH and its metabolites in human and murine samples as well as in samples from in vitro studies. These methods were substantially refined and evaluated by Köhrle and his team and led to a considerable number of analytical applications in cell cultures, animal models and large epidemiological cohorts by groups of the TTA consortium [3][4][5][6]. TH synthesis is regulated by the hypothalamic-pituitary-thyroid axis.…”

“…Besides the classical hormones T3 and T4, the biochemical properties and modes of action of new TH metabolites such as 3-iodothyronamine, thyroacetic acid or 3,5-diiodothyronine [20,21] at membrane receptors have been investigated by the Biebermann group [22,23] and at transient receptor potential channels by Mergler and team [24], in addition to first mouse and cohort analyses, hinting to a potential cardiometabolic relevance [4][5][6]25]. Unravelling the molecular basis of TH action at the level of target cells and tissues is crucial for an individualised TH replacement strategy and hereby comparative studies using rodent and human samples are helpful to identify reliable biomarkers as demonstrated by the groups of Mittag and Brabant [26].…”

Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study

“…Thyronamines (TAMs), speculated to derive from thyroid hormones (TH) through deiodination and decarboxilation, represent a novel class of signaling molecules detected in several mammal tissues, including brain, liver, pancreas and human plasma [1,2]. Among them, 3-iodothyronamine (T1AM), discovered in 2004 as the most potent agonist of traceamine associated receptor type 1 (TAAR1) [2], has extensively been studied for almost two decades, revealing to be endowed with a wide range of bio-pharmacological properties, including metabolic reprogramming and neuroprotection [3][4][5][6][7][8][9][10][11][12].…”