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Thomas S Scanlan - One of the best experts on this subject based on the ideXlab platform.
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N- and O-Acetylated 3-Iodothyronamines Have No Metabolic or Thermogenic Effects in Male Mice.
European thyroid journal, 2019Co-Authors: Sogol Gachkar, Heike Biebermann, Thomas S Scanlan, Rebecca Oelkrug, Beate Herrmann, Qian Sun, Carolin S. Hoefig, Lutz Schomburg, Jens MittagAbstract:Introduction Injection of 3-Iodothyronamine into experimental animals profoundly affects their metabolism and body temperature. As 3-Iodothyronamine is rapidly acetylated in vivo after injection, it was hypothesized that the metabolites N- or O-acetyl-3-Iodothyronamines could constitute the active hormones. Methods Adult male mice were injected once daily with one of the metabolites (5 mg/kg body weight intraperitoneally dissolved in 60% DMSO in PBS) or solvent. Metabolism was monitored by indirect calorimetry, body temperature by infrared thermography, and body composition by nuclear magnetic resonance analysis. Signaling activities in brown fat or liver were assessed by studying target gene transcription by qPCR including uncoupling protein 1 or deiodinase type 1 or 2, and Western blot. Results The markers of metabolism, body composition, or temperature tested were similar in the mice injected with solvent and those injected with one of the acetylated 3-Iodothyronamines. Conclusions In our experimental setup, N- and O-acetyl-3-Iodothyronamine do not constitute compounds contributing to the metabolic or temperature effects described for 3-Iodothyronamine. The acetylation of 3-Iodothyronamine observed in vivo may thus rather serve degradation and elimination purposes.
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Proof of concept of the electrochemical sensing of 3-Iodothyronamine (T1AM) and Thyronamine (T0AM)
ChemElectroChem, 2014Co-Authors: Luís Moreira Gonçalves, Thomas S Scanlan, Manuela M. Moreira, Carla F. Azevedo, Inês M. Valente, João Sousa, Richard G. Compton, José A. RodriguesAbstract:Recent studies have shown that, besides the well-recognized T3 and T4 hormones, there are other relevant thyroid hormones circulating in the human body. In particular, this is the case for 3-Iodothyronamine (T1AM) and thyronamine (T0AM). One of the reasons for the lack of studies showing their precise importance is the absence of analytical methodologies available. Herein, for the first time, T1AM and T0AM are electrochemically characterized. T0AM was sensed by means of a glassy carbon electrode; furthermore, T1AM was sensed both with a graphitic surface (oxidatively) as well as with mercury (reductively). For both compounds, after oxidation, it was possible to observe the reversible redox reaction concerning the benzoquinone/hydroquinone couple, thus increasing the specificity of the electroanalysis. Therefore, this work provides the basis for an ‘at-point-of-use’ electrochemical strip test for T1AM and T0AM.
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Biosynthesis of 3-Iodothyronamine (T1AM) is dependent on the sodium-iodide symporter and thyroperoxidase but does not involve extrathyroidal metabolism of T4.
Endocrinology, 2012Co-Authors: Sarah A. Hackenmueller, Maja Marchini, Alessandro Saba, Riccardo Zucchi, Thomas S ScanlanAbstract:3-Iodothyronamine (T1AM) is an endogenous thyroid hormone derivative with unknown biosynthetic origins. Structural similarities have led to the hypothesis that T1AM is an extrathyroidal metabolite of T4. This study uses an isotope-labeled T4 [heavy-T4 (H-T4)] that can be distinguished from endogenous T4 by mass spectrometry, which allows metabolites to be identified based on the presence of this unique isotope signature. Endogenous T1AM levels depend upon thyroid status and decrease upon induction of hypothyroidism. However, in hypothyroid mice replaced with H-T4, the isotope-labeled H-T3 metabolite is detected, but no isotope-labeled T1AM is detected. These data suggest that T1AM is not an extrathyroidal metabolite of T4, yet is produced by a process that requires the same biosynthetic factors necessary for T4 synthesis.
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Identification and quantification of 3-Iodothyronamine metabolites in mouse serum using liquid chromatography-tandem mass spectrometry
J Chromatogr A, 2012Co-Authors: Sarah A. Hackenmueller, Thomas S ScanlanAbstract:3-Iodothyronamine (T(1)AM) is an endogenous derivative of thyroxine. Recently there have been numerous reports of analytical methods to quantify endogenous T(1)AM levels, but substantial discrepancies in concentration depending on the method of analysis (LC-MS/MS or immunoassay) suggest endogenous T(1)AM may be covalently modified in vivo. Using information dependent acquisition methods to perform unbiased scans for T(1)AM metabolites following a single IP injection in mice, we have identified O-sulfonate-T(1)AM, N-acetyl-T(1)AM and T(1)AM-glucuronide as conjugates occurring in vivo, as well as the oxidatively deaminated 3-iodothyroacetic acid and non-iodinated thyroacetic acid. 3-iodothyroacetic acid, O-sulfonate-T(1)AM and T(1)AM-glucuronide are present in serum at greater concentrations that unmodified T(1)AM and all metabolites are extensively distributed to tissues. These results suggest covalent modifications of T(1)AM may play a critical role in regulating distribution and biological activity of T(1)AM, and analytical methods to quantify endogenous T(1)AM should be able to account for these metabolites as well.
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ApoB-100-containing lipoproteins are major carriers of 3-Iodothyronamine in circulation
Journal of Biological Chemistry, 2012Co-Authors: Gouriprasanna Roy, Ekaterina Placzek, Thomas S ScanlanAbstract:3-Iodothyronamine (T(1)AM) is a biogenic amine derivative of thyroid hormone present in tissue and blood of vertebrates. Approximately 99% of the circulating thyroid hormones are bound to plasma proteins, including three major thyroid hormone-binding proteins, and the question arises as to whether circulating T(1)AM is also bound to serum factors. We report here that T(1)AM is largely bound to a single protein component of human serum. Using T(1)AM-affinity chromatography, we isolated this protein, and sequence analysis identified it as apolipoprotein B-100 (apoB-100), the protein component of several low density lipoprotein particles. Consistent with this finding, we demonstrate that >90% of specifically bound T(1)AM in human serum resides in the apoB-100-containing low density lipoprotein fraction. T(1)AM reversibly binds to apoB-100-containing lipoprotein particles with an equilibrium dissociation constant (K(D)) of 17 nm and a T(1)AM/apoB-100 stoichiometry of 1:1. Competition binding assays demonstrate that this binding site is highly selective for T(1)AM. Intracellular T(1)AM uptake is significantly enhanced by apoB-100-containing lipoprotein particles. Modest enhancements to apoB-100 cellular uptake and secretion by T(1)AM were observed; however, multidose T(1)AM treatment did not affect lipid or lipoprotein inventory in vivo. Thus, it appears that apoB-100 serves as a carrier of circulating T(1)AM and affords a novel mechanism by which T(1)AM gains entry to cells.
Riccardo Zucchi - One of the best experts on this subject based on the ideXlab platform.
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Exogenous 3-Iodothyronamine Rescues the Entorhinal Cortex from β-Amyloid Toxicity.
Thyroid : official journal of the American Thyroid Association, 2019Co-Authors: Alice Accorroni, Sandra Ghelardoni, Alessandro Saba, Sabina Frascarelli, Martina Sabatini, Grazia Rutigliano, Marco Borsò, Elena Novelli, Lavinia Bandini, Riccardo ZucchiAbstract:Background: A novel form of thyroid hormone (TH) signaling is represented by 3-Iodothyronamine (T1AM), an endogenous TH derivative that interacts with specific molecular targets, including trace am...
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Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases.
Expert opinion on therapeutic targets, 2018Co-Authors: Michael D. Schwartz, Riccardo Zucchi, Stefano Espinoza, Juan J. Canales, I. Sukhanov, Raul R. GainetdinovAbstract:ABSTRACTIntroduction: The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a trace amine-sensitive G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of trace amine signaling.Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-Iodothyronamine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopaminergic signaling is likely to underlie many of its CNS effects. How...
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Lipolytic effects of endogenous 3-Iodothyronamine (T1AM) and synthetic analog SG-2 in vivo and in cultured adipocytes
Endocrine Abstracts, 2017Co-Authors: Martina Sabatini, Riccardo Zucchi, Michael Rogowski, Fariba M. Assadi-porter, Ebru S. Selen Alpergin, Grazia ChielliniAbstract:3-Iodothyronamine (T1AM) is a hormone like molecule structurally similar to TH, that has been reported to modulate energy metabolism by favoring lipid over glucose catabolism. To better understand the role played by T1AM on the regulation of lipid metabolism, in the present study we administered spontaneously obese mice with T1AM at two different dosages (10 and 25 mg/kg per day) for 7 days and the effects on body weight (BW) and lipid profiles were examined. In addition a fluoro-labeled version of T1AM (FL-T1AM) was synthesized and utilized to assess T1AM intracellular localization in 3T3-L1 mouse adipocytes.\ud \ud Administration of 10 or 25 mg/kg per day T1AM showed a BW loss of 10% or 18% of initial BW by day 7 of treatment. T1AM treatment at both dosages produced a significant increase in total plasma triglycerides (P
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Cardiac actions of thyroid hormone metabolites
Molecular and cellular endocrinology, 2017Co-Authors: Grazia Rutigliano, Riccardo ZucchiAbstract:Thyroid hormones (THs) have a major role in regulating cardiac function. Their classical mechanism of action is genomic. Recent findings have broadened our knowledge about the (patho)physiology of cardiac regulation by THs, to include non-genomic actions of THs and their metabolites (THM). This review provides an overview of classical and non-classical cardiac effects controlled by: i) iodothyronines (thyroxine, T4; 3,5,3’-triiodothyronine,T3; 3, 5-diiodothyronine, T2); ii) thyronamines (thyronamine, T0AM; 3-Iodothyronamine, T1AM); and iii) iodothyroacetic acids (3, 5, 3′, 5’-tetraiodothyroacetic acid, tetrac; 3, 5, 3’-triiodothyroacetic acid, triac; 3-iodothyroacetic acid, TA1). Whereas iodothyronines enhance both diastolic and systolic function and heart rate, thyronamines were observed to have negative inotropic and chronotropic effects and might function as a brake with respect to THs, although their physiological role is unclear. Moreover, thyronamines showed a cardioprotective effect at physiological concentrations. The cardiac effects of iodothyroacetic acids seem to be limited and need to be elucidated.
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Thyronamines and Analogues - The Route from Rediscovery to Translational Research on Thyronergic Amines
Molecular and cellular endocrinology, 2017Co-Authors: Grazia Chiellini, Martina Sabatini, Lorenza Bellusci, Riccardo ZucchiAbstract:Thyronamines are a novel class of endogenous signaling compounds, structurally related to thyroid hormones (THs). Specific thyronamines, particularly 3-Iodothyronamine (T1AM), stimulate with nanomolar affinity trace amine-associated receptor 1 (TAAR1), a G protein-coupled membrane receptor, and may also interact with other TAAR subtypes (particularly TAAR5), adrenergic receptors (particularly α2 receptors), amine transporters, and mitochondrial proteins. In addition to its structural similarities with THs, T1AM also contains the arylethylamine scaffold as in monoamine neurotransmitters, implicating an intriguing role for T1AM as both a neuromodulator and a hormone-like molecule constituting a part of thyroid hormone signaling. A large number of T1AM derivatives have already been synthesized. We discuss the different chemical strategies followed to obtain thyronamine analogues, their potency at TAAR1, and their structure-activity relationship. Preliminary characterization of the functional effects of these synthetic compounds is also provided.
Grazia Chiellini - One of the best experts on this subject based on the ideXlab platform.
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3-Iodothyronamine Affects Thermogenic Substrates' Mobilization in Brown Adipocytes.
Biology, 2020Co-Authors: Manuela Gencarelli, Grazia Chiellini, Annunziatina Laurino, Elisa Landucci, Daniela Buonvicino, Costanza Mazzantini, Laura RaimondiAbstract:We investigated the effect of 3-Iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance.
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Lipolytic effects of endogenous 3-Iodothyronamine (T1AM) and synthetic analog SG-2 in vivo and in cultured adipocytes
Endocrine Abstracts, 2017Co-Authors: Martina Sabatini, Riccardo Zucchi, Michael Rogowski, Fariba M. Assadi-porter, Ebru S. Selen Alpergin, Grazia ChielliniAbstract:3-Iodothyronamine (T1AM) is a hormone like molecule structurally similar to TH, that has been reported to modulate energy metabolism by favoring lipid over glucose catabolism. To better understand the role played by T1AM on the regulation of lipid metabolism, in the present study we administered spontaneously obese mice with T1AM at two different dosages (10 and 25 mg/kg per day) for 7 days and the effects on body weight (BW) and lipid profiles were examined. In addition a fluoro-labeled version of T1AM (FL-T1AM) was synthesized and utilized to assess T1AM intracellular localization in 3T3-L1 mouse adipocytes.\ud \ud Administration of 10 or 25 mg/kg per day T1AM showed a BW loss of 10% or 18% of initial BW by day 7 of treatment. T1AM treatment at both dosages produced a significant increase in total plasma triglycerides (P
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Thyronamines and Analogues - The Route from Rediscovery to Translational Research on Thyronergic Amines
Molecular and cellular endocrinology, 2017Co-Authors: Grazia Chiellini, Martina Sabatini, Lorenza Bellusci, Riccardo ZucchiAbstract:Thyronamines are a novel class of endogenous signaling compounds, structurally related to thyroid hormones (THs). Specific thyronamines, particularly 3-Iodothyronamine (T1AM), stimulate with nanomolar affinity trace amine-associated receptor 1 (TAAR1), a G protein-coupled membrane receptor, and may also interact with other TAAR subtypes (particularly TAAR5), adrenergic receptors (particularly α2 receptors), amine transporters, and mitochondrial proteins. In addition to its structural similarities with THs, T1AM also contains the arylethylamine scaffold as in monoamine neurotransmitters, implicating an intriguing role for T1AM as both a neuromodulator and a hormone-like molecule constituting a part of thyroid hormone signaling. A large number of T1AM derivatives have already been synthesized. We discuss the different chemical strategies followed to obtain thyronamine analogues, their potency at TAAR1, and their structure-activity relationship. Preliminary characterization of the functional effects of these synthetic compounds is also provided.
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Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study.
Journal of Medicinal Chemistry, 2016Co-Authors: Grazia Chiellini, Giulia Nesi, Simona Sestito, Sara Chiarugi, Massimiliano Runfola, Stefano Espinoza, Martina Sabatini, Lorenza Bellusci, Annunziatina Laurino, Elena CicheroAbstract:The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-Iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (1–16) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2...
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Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study
2016Co-Authors: Grazia Chiellini, Giulia Nesi, Simona Sestito, Sara Chiarugi, Massimiliano Runfola, Stefano Espinoza, Martina Sabatini, Lorenza Bellusci, Annunziatina Laurino, Elena CicheroAbstract:The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-Iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (1–16) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2, showed potent functional activity in in vitro and in vivo models
Josef Köhrle - One of the best experts on this subject based on the ideXlab platform.
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3-Iodothyronamine—A Thyroid Hormone Metabolite With Distinct Target Profiles and Mode of Action
Endocrine reviews, 2019Co-Authors: Josef Köhrle, Heike BiebermannAbstract:The rediscovery of the group of thyronamines (TAMs), especially the first detailed description of their most prominent congener 3-Iodothyronamine (3T1AM) 14 years ago, boosted research on this thyroid hormone metabolite tremendously. TAMs exert actions partly opposite to and distinct from known functions of thyroid hormones. These fascinating metabolic, anapyrexic, cytoprotective, and brain effects quickly evoked the hope to use hormone-derived TAMs as a therapeutic option. The G protein-coupled receptor (GPCR) TAAR1, a member of the trace amine-associated receptor (TAAR) family, was identified as the first target and effector of TAM action. The initial enthusiasm on pharmacological actions of exogenous TAMs elicited many questions, such as sites of biosynthesis, analytics, modes of action, inactivation, and role of TAMs in (patho)physiology. Meanwhile, it became clear that TAMs not only interact with TAAR1 or other TAAR family members but also with several aminergic receptors and non-GPCR targets such as transient receptor potential channels, mitochondrial proteins, and the serum TAM-binding protein apolipoprotein B100, thus classifying 3T1AM as a multitarget ligand. The physiological mode of action of TAMs is still controversial because regulation of endogenous TAM production and the sites of its biosynthesis are not fully elucidated. Methods for 3T1AM analytics need further validation, as they revealed different blood and tissue concentrations depending on detection principles used such as monoclonal antibody-based immunoassay vs liquid chromatography- matrix-assisted laser desorption/ionization mass spectrometry or time-of-flight mass spectrometry. In this review, we comprehensively summarize and critically evaluate current basic, translational, and clinical knowledge on 3T1AM and its main metabolite 3-iodothyroacetic acid, focusing on endocrine-relevant aspects and open but highly challenging issues.
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Association Between 3-Iodothyronamine (T1am) Concentrations and Left Ventricular Function in Chronic Heart Failure.
The Journal of clinical endocrinology and metabolism, 2018Co-Authors: Jeppe Lerche La Cour, Josef Köhrle, Ina Lehmphul, Heidi M Christensen, Caroline Kistorp, Birte Nygaard, Jens FaberAbstract:CONTEXT Thyroid hormone metabolites might affect the heart. The endogenous aminergic metabolite 3-Iodothyronamine (T1am) reduces left ventricular ejection fraction (LVEF) in rodents. OBJECTIVE To investigate concentration of T1am and its association with LVEF and biomarkers of heart function in patients with chronic heart failure (CHF) without thyroid disease, including patients with cardiac cachexia (nonedematous weight loss >5% over 6 months). METHODS Cross-sectional study. CHF was characterized by LVEF 45%. T1am was measured by a monoclonal antibody-based chemiluminescence immunoassay. N-amino terminal pro-BNP (NT-proBNP) concentrations were also analyzed. RESULTS Mean (SD) LVEF: CAC, 32 ± 9%; non-CAC, 38 ± 8%; and C, 60 ± 8% (P < 0.0001). TSH, T4, and T3 levels did not differ between groups and did not correlate to T1am. Serum T1am (nmol/L) concentrations were higher in CHF: CAC (mean ± SD), 12.4 ± 6.6; non-CAC, 9.1 ± 5; and C, 7.3 ± 2.9. A negative association between T1am and LVEF was present after adjusting for sex, age, T3, and estimated glomerular filtration rate (P = 0.03). Further, serum T1am levels tended to be associated with NT-proBNP (P = 0.053). CONCLUSION Serum T1am levels were increased in patients with CHF and numerically highest (although nonsignificant) in patients with cardiac cachexia. Increasing T1am concentrations were independently associated with reduced LVEF, suggesting a direct effect on the human heart.
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3-Iodothyronamine reduces insulin secretion in vitro via a mitochondrial mechanism.
Molecular and cellular endocrinology, 2017Co-Authors: Ina Lehmphul, Carolin S. Hoefig, Josef KöhrleAbstract:Abstract Purpose 3-Iodothyronamine (3-T1AM), a decarboxylated and deiodinated thyroid hormone metabolite, leads at pharmacological doses to hypoinsulinemia, hyperglucagonemia and hyperglycemia in vivo. As the pancreatic Langerhans islets express thyroid hormone transmembrane transporters (THTT), we tested the hypothesis that not only plasma membrane-mediated 3-T1AM binding to and activation of G-protein coupled receptors, but also 3-T1AM metabolite(s) generated by 3-T1AM uptake and metabolism might decrease glucose-stimulated insulin secretion (GSIS). Methods Murine pancreatic β-cells MIN6 were characterized for gene expression of THTT, deiodinases and monoamine oxidases. 3-T1AM uptake and intracellular metabolism to the corresponding 3-iodothyroacetic acid were analysed by liquid-chromatography tandem mass spectrometry (LC-MS/MS) at different time points in cells as well as the conditioned medium. Mitochondrial activity, especially ATP-production, was monitored real-time after 3-T1AM application using Seahorse Bioanalyzer technique. Effect of 3-T1AM on GSIS into the culture medium was assayed by ELISA. Results MIN6 cells express classical THTT, proposed to transport 3-T1AM, as well as 3-T1AM metabolizing enzymes comparable to murine primary pancreatic islets. 3-T1AM accumulates in MIN6 cells and is metabolized by intracellular MaoB to 3-iodothyroacetic, which in turn is rapidly exported. 3-T1AM decreases mitochondrial ATP-production concentration dependently. GSIS is diminished by 3-T1AM treatment. Using LC-MS/MS, no further 3-T1AM metabolites except 3-iodothyroacetic were detectable. Conclusions This data provides a first link between cellular 3-T1AM uptake and regulation of mitochondrial energy metabolism in s-cells, resulting in reduced insulin secretion. We conclude that MIN6 is an appropriate cell model to study 3-T1AM-dependent (intra-)cellular biochemical mechanisms affecting insulin production in vitro.
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Circulating 3-T1AM and 3,5-T2 in critically ill patients: a cross-sectional observational study
Thyroid : official journal of the American Thyroid Association, 2016Co-Authors: Lies Langouche, Josef Köhrle, Ina Lehmphul, Sarah Vander Perre, Greet Van Den BergheAbstract:Background: Critical illness is hallmarked by low circulating thyroxine (T4) and triiodothyronine (T3) concentrations, in the presence of elevated reverse T3 (rT3) and low-normal thyrotropin (TSH), referred to as nonthyroidal illness (NTI). Thyroid hormone (TH) metabolism is substantially increased during NTI, in part explained by enhanced deiodinase 3 (D3) activity. T4- and T3-sulfate concentrations are elevated, due to suppressed D1 activity in the presence of unaltered sulfotransferase activity, and 3,3′-diiodothyronine (3,3′-T2) concentrations are normal. To elucidate further the driving forces behind increased TH metabolism during NTI, two other potential T4 metabolites—3,5-diiodothyronine (3,5-T2) and 3-Iodothyronamine (3-T1AM)—were measured and related to their potential TH precursors. Methods: Morning blood samples were collected cross-sectionally from 83 critically ill patients on a University Hospital intensive care unit and from 38 demographically matched healthy volunteers. Serum TH and bindin...
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Differential Modulation of Adrenergic Receptor Signaling by Octopamine, Tyramine, Phenylethylamine, and 3-Iodothyronamine
Trace Amines and Neurological Disorders, 2016Co-Authors: Gunnar Kleinau, Noushafarin Khajavi, Josef Köhrle, Heike BiebermannAbstract:Trace amine-associated receptors (TAARs) are family A G-protein-coupled receptors. TAAR1 interacts with trace amines such as tyramine, octopamine, β-phenylethylamine, and with 3-Iodothyronamine (3-T1AM), a signaling molecule with structural similarities to thyroid hormones (TH). These ligands were recently investigated in regard to their effects on the signaling properties of β-adrenergic receptors 1 and 2, or the α2A-adrenergic receptor. These receptors share a high degree of homology in protein structure and amino acid constitution compared with TAAR1. In vitro studies have deciphered differentially regulated signaling pathways at adrenergic receptors by these ligands that act either orthosteric or allosteric with antagonistic, modulatory, or agonistic capacities. Accordingly, these ligands cause diverse effects at different aminergic receptors including adrenergic receptors. This chapter summarizes molecular insights into the interplay between specific trace amines, 3-T1AM, and adrenergic receptors.
Heike Biebermann - One of the best experts on this subject based on the ideXlab platform.
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N- and O-Acetylated 3-Iodothyronamines Have No Metabolic or Thermogenic Effects in Male Mice.
European thyroid journal, 2019Co-Authors: Sogol Gachkar, Heike Biebermann, Thomas S Scanlan, Rebecca Oelkrug, Beate Herrmann, Qian Sun, Carolin S. Hoefig, Lutz Schomburg, Jens MittagAbstract:Introduction Injection of 3-Iodothyronamine into experimental animals profoundly affects their metabolism and body temperature. As 3-Iodothyronamine is rapidly acetylated in vivo after injection, it was hypothesized that the metabolites N- or O-acetyl-3-Iodothyronamines could constitute the active hormones. Methods Adult male mice were injected once daily with one of the metabolites (5 mg/kg body weight intraperitoneally dissolved in 60% DMSO in PBS) or solvent. Metabolism was monitored by indirect calorimetry, body temperature by infrared thermography, and body composition by nuclear magnetic resonance analysis. Signaling activities in brown fat or liver were assessed by studying target gene transcription by qPCR including uncoupling protein 1 or deiodinase type 1 or 2, and Western blot. Results The markers of metabolism, body composition, or temperature tested were similar in the mice injected with solvent and those injected with one of the acetylated 3-Iodothyronamines. Conclusions In our experimental setup, N- and O-acetyl-3-Iodothyronamine do not constitute compounds contributing to the metabolic or temperature effects described for 3-Iodothyronamine. The acetylation of 3-Iodothyronamine observed in vivo may thus rather serve degradation and elimination purposes.
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3-Iodothyronamine Induces Diverse Signaling Effects at Different Aminergic and Non-Aminergic G-Protein Coupled Receptors
Experimental and clinical endocrinology & diabetes : official journal German Society of Endocrinology [and] German Diabetes Association, 2019Co-Authors: Heike Biebermann, Gunnar KleinauAbstract:The thyroid hormone metabolite 3-Iodothyronamine (3-T1AM) exerts diverse physiological reactions such as a decrease of body temperature, and negative inotropic and chronotropic effects. This observed pleomorphic effect in physiology can be barely explained by interaction with only one target protein such as the trace-amine receptor 1 (TAAR1), a class A G-protein coupled receptor (GPCR). Moreover, Taar1 knock-out mice still react to 3-T1AM through physiological responses with a rapid decrease in body temperature. These facts propelled our group and others to search for further targets for this molecule. The group of TAARs evolved early in evolution and, according to sequence similarities, they are closely related to adrenoceptors and other aminergic receptors. Therefore, several of these receptors were characterized by their potential to interplay with 3-T1AM. Indeed, 3-T1AM acts as a positive allosteric modulator on the beta2-adrenoceptor (ADRB2) and as a biased agonist on the serotonin receptor 1B (5HT1b) and the alpha2-adrenoceptor (ADRA2A). In addition, 3-T1AM was reported to be a weak antagonist at a non-aminergic muscarinic receptor (M3). These findings impressively reflect that such trace amines can unselectively and simultaneously function at different receptors expressed by one cell or at different tissues. In conclusion, the role of 3-T1AM is hypothesized to concert the fine-tuning of specific cell reactions by the accentuation of certain pathways dependent on distinct receptors. 3-T1AM acts as a regulator of signals by blocking, modulating, or inducing simultaneously distinct intracellular signaling cascades via different GPCRs.
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3-Iodothyronamine—A Thyroid Hormone Metabolite With Distinct Target Profiles and Mode of Action
Endocrine reviews, 2019Co-Authors: Josef Köhrle, Heike BiebermannAbstract:The rediscovery of the group of thyronamines (TAMs), especially the first detailed description of their most prominent congener 3-Iodothyronamine (3T1AM) 14 years ago, boosted research on this thyroid hormone metabolite tremendously. TAMs exert actions partly opposite to and distinct from known functions of thyroid hormones. These fascinating metabolic, anapyrexic, cytoprotective, and brain effects quickly evoked the hope to use hormone-derived TAMs as a therapeutic option. The G protein-coupled receptor (GPCR) TAAR1, a member of the trace amine-associated receptor (TAAR) family, was identified as the first target and effector of TAM action. The initial enthusiasm on pharmacological actions of exogenous TAMs elicited many questions, such as sites of biosynthesis, analytics, modes of action, inactivation, and role of TAMs in (patho)physiology. Meanwhile, it became clear that TAMs not only interact with TAAR1 or other TAAR family members but also with several aminergic receptors and non-GPCR targets such as transient receptor potential channels, mitochondrial proteins, and the serum TAM-binding protein apolipoprotein B100, thus classifying 3T1AM as a multitarget ligand. The physiological mode of action of TAMs is still controversial because regulation of endogenous TAM production and the sites of its biosynthesis are not fully elucidated. Methods for 3T1AM analytics need further validation, as they revealed different blood and tissue concentrations depending on detection principles used such as monoclonal antibody-based immunoassay vs liquid chromatography- matrix-assisted laser desorption/ionization mass spectrometry or time-of-flight mass spectrometry. In this review, we comprehensively summarize and critically evaluate current basic, translational, and clinical knowledge on 3T1AM and its main metabolite 3-iodothyroacetic acid, focusing on endocrine-relevant aspects and open but highly challenging issues.
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3-Iodothyronamine Activates a Set of Membrane Proteins in Murine Hypothalamic Cell Lines.
Frontiers in endocrinology, 2018Co-Authors: Julia Bräunig, Heike Biebermann, Stefan Mergler, Carolin S. Hoefig, Jens Mittag, Sabine Jyrch, Mark Rosowski, Noushafarin KhajaviAbstract:3-Iodothyronamine (3-T1AM) is an endogenous thyroid hormone metabolite. The profound pharmacological effects of 3-T1AM on energy metabolism and thermal homeostasis have raised interest to elucidate its signaling properties in tissues that pertain to metabolic regulation and thermogenesis. Previous studies identified G protein-coupled receptors (GPCRs) and transient receptor potential channels (TRPs) as targets of 3-T1AM in different cell types. These two superfamilies of membrane proteins are largely expressed in tissue which influences energy balance and metabolism. As the first indication that 3-T1AM virtually modulates the function of the neurons in hypothalamus, we observed that intraperitoneal administration of 50 mg/kg bodyweight of 3-T1AM significantly increased the c-FOS activation in the paraventricular nucleus (PVN) of C57BL/6 mice. To elucidate the underlying mechanism behind this 3-T1AM-induced signalosome, we used three different murine hypothalamic cell lines, which are all known to express PVN markers, GT1-7, mHypoE-N39 (N39) and mHypoE-N41 (N41). Various aminergic GPCRs, which are the known targets of 3-T1AM, as well as numerous members of TRP channel superfamily, are expressed in these cell lines. Effects of 3-T1AM on activation of GPCRs were tested for the two major signaling pathways, the action of Gαs/adenylyl cyclase and Gi/o. Here, we demonstrated that this thyroid hormone metabolite has no significant effect on Gi/o signaling and only a minor effect on the Gαs/adenylyl cyclase pathway, despite the expression of known GPCR targets of 3-T1AM. Next, to test for other potential mechanisms involved in 3-T1AM-induced c-FOS activation in PVN, we evaluated the effect of 3-T1AM on the intracellular Ca2+ concentration and whole-cell currents. The fluorescence-optic measurements showed a significant increase of intracellular Ca2+ concentration in the three cell lines in the presence of 10 μM 3-T1AM. Furthermore, this thyroid hormone metabolite led to an increase of whole-cell currents in N41 cells. Interestingly, the TRPM8 selective inhibitor (10 μM AMTB) reduced the 3-T1AM stimulatory effects on cytosolic Ca2+ and whole-cell currents. Our results suggest that the profound pharmacological effects of 3-T1AM on selected brain nuclei of murine hypothalamus, which are known to be involved in energy metabolism and thermoregulation, might be partially attributable to TRP channel activation in hypothalamic cells.
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3-Iodothyronamine, a Novel Endogenous Modulator of Transient Receptor Potential Melastatin 8?
Frontiers in Endocrinology, 2017Co-Authors: Noushafarin Khajavi, Stefan Mergler, Heike BiebermannAbstract:The decarboxylated and deiodinated thyroid hormone derivative, 3-Iodothyronamine (3-T1AM) is suggested to be involved in energy metabolism and thermoregulation. G protein-coupled receptors (GPCRs) are known as the main targets for 3-T1AM; however, transient receptor potential channels (TRPs) were also recently identified as new targets of 3-T1AM. This article reviews the current knowledge of a putative novel role of 3-T1AM in the modulation of TRPs. Specifically, the TRP melastatin 8 (TRPM8) was identified as a target of 3-T1AM in different cell types including neoplastic cells, whereby 3-T1AM significantly increased cytosolic Ca2+ through TRPM8 activation. Similarly, the β-adrenergic receptor is involved in 3-T1AM-induced Ca2+ influx. Therefore, it has been suggested that 3-T1AM-induced Ca2+ mobilization might be due to β-adrenergic receptor/TRPM8 channel interaction, which add to the complexity of GPCR regulation by TRPs. It has been revealed that TRPM8 activation leads to a decline in TRPV1 activity, which may be of therapeutic benefit in clinical circumstances such as treatment of TRPV1-mediated inflammatory hyperalgesia, colitis, and dry eye syndrome. This review also summarizes the inverse association between changes in TRPM8 and TRPV1 activity after 3-T1AM stimulation. This finding prompted further detailed investigations of the interplay between 3-T1AM and the GPCR/TRPM8 axis, and indicated the probability of additional GPCR/TRP constellations that are modulated by this thyroid hormone derivative.
