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Josef Köhrle - One of the best experts on this subject based on the ideXlab platform.
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Analysis of Human TAAR8 and Murine Taar8b Mediated Signaling Pathways and Expression Profile
International Journal of Molecular Sciences, 2014Co-Authors: Jessica Mühlhaus, Juliane Dinter, Daniela Nürnberg, Maren Depke, Janine Golchert, Chun-xia Yi, Silke Morin, Maren Rehders, Georg Homuth, Josef KöhrleAbstract:The thyroid Hormone Derivative 3-iodothyronamine (3-T1AM) exerts metabolic effects in vivo that contradict known effects of thyroid Hormones. 3-T1AM acts as a trace amine-associated receptor 1 (TAAR1) agonist and activates Gs signaling in vitro. Interestingly, 3-T1AM-meditated in vivo effects persist in Taar1 knockout-mice indicating that further targets of 3-T1AM might exist. Here, we investigated another member of the TAAR family, the only scarcely studied mouse and human trace-amine-associated receptor 8 (Taar8b, TAAR8). By RT-qPCR and locked-nucleic-acid (LNA) in situ hybridization, Taar8b expression in different mouse tissues was analyzed. Functionally, we characterized TAAR8 and Taar8b with regard to cell surface expression and signaling via different G-protein-mediated pathways. Cell surface expression was verified by ELISA, and cAMP accumulation was quantified by AlphaScreen for detection of Gs and/or Gi/o signaling. Activation of G-proteins Gq/11 and G12/13 was analyzed by reporter gene assays. Expression analyses revealed at most marginal Taar8b expression and no gender differences for almost all analyzed tissues. In heart, LNA-in situ hybridization demonstrated the absence of Taar8b expression. We could not identify 3-T1AM as a ligand for TAAR8 and Taar8b, but both receptors were characterized by a basal Gi/o signaling activity, a so far unknown signaling pathway for TAARs.
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Analysis of Human TAAR8 and Murine Taar8b Mediated Signaling Pathways and Expression Profile
International Journal of Molecular Sciences, 2014Co-Authors: Jessica Mühlhaus, Juliane Dinter, Daniela Nürnberg, Maren Depke, Janine Golchert, Chun-xia Yi, Silke Morin, Maren Rehders, Georg Homuth, Josef KöhrleAbstract:The thyroid Hormone Derivative 3-iodothyronamine (3-T1AM) exerts metabolic effects in vivo that contradict known effects of thyroid Hormones. 3-T1AM acts as a trace amine-associated receptor 1 (TAAR1) agonist and activates Gs signaling in vitro. Interestingly, 3-T1AM-meditated in vivo effects persist in Taar1 knockout-mice indicating that further targets of 3-T1AM might exist. Here, we investigated another member of the TAAR family, the only scarcely studied mouse and human trace-amine-associated receptor 8 (Taar8b, TAAR8). By RT-qPCR and locked-nucleic-acid (LNA) in situ hybridization, Taar8b expression in different mouse tissues was analyzed. Functionally, we characterized TAAR8 and Taar8b with regard to cell surface expression and signaling via different G-protein-mediated pathways. Cell surface expression was verified by ELISA, and cAMP accumulation was quantified by AlphaScreen for detection of Gs and/or Gi/o signaling. Activation of G-proteins Gq/11 and G12/13 was analyzed by reporter gene assays. Expression analyses revealed at most marginal Taar8b expression and no gender differences for almost all analyzed tissues. In heart, LNA-in situ hybridization demonstrated the absence of Taar8b expression. We could not identify 3-T1AM as a ligand for TAAR8 and Taar8b, but both receptors were characterized by a basal Gi/o signaling activity, a so far unknown signaling pathway for TAARs.
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Aspects of 3-iodothyronamine (3T1AM) induced signaling by human and mouse trace amine-associated receptor 5 (TAAR5)
Experimental and Clinical Endocrinology & Diabetes, 2014Co-Authors: Jessica Mühlhaus, Juliane Dinter, Daniela Nürnberg, Chun-xia Yi, Carolin L. Piechowski, Anne Muller, Annette Gruters, Josef Köhrle, Matthias H. Tschöp, H KrudeAbstract:The thyroid Hormone Derivative 3-iodothyronamine (3T1AM) is an agonist for trace amine-associated receptor 1 (TAAR1). Application of 3T1AM in rodents results in a variety of effects, including decreased body temperature. Taar1-/- mice still show these effects, excluding Taar1 as primary mediator of 3T1AM induced action in vivo. Because of its role as potential treatment option for stroke patients, possible targets and effects of 3T1AM in humans are of medical interest. Here we investigated the human (hTAAR5) and mouse Taar5 (mTaar5) as potential target to explain 3T1AM effects in Taar1-/- mice. In situ hybridization for mTaar1 and mTaar5 revealed overlapping expression profiles in the amygdala and VMH. Next, we investigated several signaling pathways of mTaar5 and hTAAR5. We confirmed previously reported data that the volatile amine dimethylethylamine is an agonist for Gs activation by mTaar5, however, not for hTAAR5. Further investigations revealed a basal tone of ERK and Gq activation for hTAAR5 and mTaar5 and additional basal Gs activity for mTaar5 mediating cAMP accumulation. In response to 3T1AM, no signaling via Gs, Gq, Gi, G12/13 and ERK was observed for hTAAR5 and mTaar5, while 3T1AM acted as inverse agonist on hTAAR5 by decreasing the basal tone of IP3 accumulation and ERK. To elucidate the particular determinants involved in signaling differences between hTAAR5 and mTaar5 we created chimeric receptors, aiming to transfer murine signaling properties to hTAAR5. We identified 6 amino acids in the ligand binding and G protein-coupling region to be involved. Our data demonstrated that caution is needed when transferring signaling properties of mTaar5 to the human situation. While observed pharmacological effects of 3T1AM on Taar1-/- mice are likely not related to mTaar5, according to our in vitro data, hTAAR5 functions as a target for 3T1AM and exhibits inhibitory 3T1AM effects on Gq and ERK signaling. Supported by DFG-SPP1629 ThyroidTransAct
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selective labelling and inactivation of creatine kinase isoenzymes by the thyroid Hormone Derivative n bromoacetyl 3 3 5 tri iodo l thyronine
Biochemical Journal, 1993Co-Authors: Markus Wyss, Josef KöhrleAbstract:Besides their well-known regulation of transcription by binding to nuclear receptors, thyroid Hormones have been suggested to have direct effects on mitochondria. In a previous study, incubation of rat heart mitochondria with 125I-labelled N-bromoacetyl-3,3′,5-tri-iodo-L-thyronine (BrAcT3), a thyroid Hormone Derivative with an alkylating side chain, resulted in the selective labelling of a protein doublet around M(r) 45,000 on SDS/polyacrylamide gels [Rasmussen, Kohrle, Rokos and Hesch (1989) FEBS Lett. 255, 385-390]. Now, this protein doublet has been identified as mitochondrial creatine kinase (Mi-CK). Immunoblotting experiments with the cytoplasmic and mitochondrial fractions of rat heart, brain and liver, as well as inactivation studies with the purified chicken CK isoenzymes have further demonstrated that all four CK isoenzymes (Mia-, Mib-, M- and B-CK) are indeed selectively labelled by BrAcT3. However, in contrast with their bromoalkyl Derivatives, thyroid Hormones themselves did not compete for CK labelling, suggesting that not the thyroid Hormone moiety but rather the bromoacetyl-driven alkylation of the highly reactive ‘essential’ thiol group of CK accounts for this selective labelling. Therefore the assumption that CK isoenzymes are thyroid-Hormone-binding proteins has to be dismissed. Instead, bromoacetyl-based reagents may allow a very specific covalent modification and inactivation of CK isoenzymes in vitro and in vivo.
Thomas S Scanlan - One of the best experts on this subject based on the ideXlab platform.
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effects of acute microinjections of the thyroid Hormone Derivative 3 iodothyronamine to the preoptic region of adult male rats on sleep thermoregulation and motor activity
Hormones and Behavior, 2013Co-Authors: Thomas D James, Steven X Moffett, Thomas S Scanlan, Joseph V MartinAbstract:Abstract The decarboxylated thyroid Hormone Derivative 3-iodothyronamine (T1AM) has been reported as having behavioral and physiological consequences distinct from those of thyroid Hormones. Here, we investigate the effects of T1AM on EEG-defined sleep after acute administration to the preoptic region of adult male rats. Our laboratory recently demonstrated a decrease in EEG-defined sleep after administration of 3,3′,5-triiodo- l -thyronine (T3) to the same brain region. After injection of T1AM or vehicle solution, EEG, EMG, activity, and core body temperature were recorded for 24 h. Sleep parameters were determined from EEG and EMG data. Earlier investigations found contrasting systemic effects of T3 and T1AM, such as decreased heart rate and body temperature after intraperitoneal T1AM injection. However, nREM sleep was decreased in the present study after injections of 1 or 3 μg T1AM, but not after 0.3 or 10 μg, closely mimicking the previously reported effects of T3 administration to the preoptic region. The biphasic dose–response observed after either T1AM or T3 administration seems to indicate shared mechanisms and/or functions of sleep regulation in the preoptic region. Consistent with systemic administration of T1AM, however, microinjection of T1AM decreased body temperature. The current study is the first to show modulation of sleep by T1AM, and suggests that T1AM and T3 have both shared and independent effects in the adult mammalian brain.
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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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Transport of thyroid Hormones is selectively inhibited by 3-iodothyronamine
Molecular BioSystems, 2010Co-Authors: Alexandra G Ianculescu, Edith C. H. Friesema, Theo J. Visser, Kathleen M. Giacomini, Thomas S ScanlanAbstract:Thyroid Hormone transporters are responsible for the cellular uptake of thyroid Hormones, which is a prerequisite for their subsequent metabolism and action at nuclear thyroid Hormone receptors. A recently discovered thyroid Hormone Derivative, 3-iodothyronamine (T1AM), has distinct biological effects that are opposite those of thyroid Hormone. Here we investigate the effects of T1AM on thyroid Hormone transporters using COS-1 cells transfected with the multispecific organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 1C1, as well as the specific thyroid Hormone transporters MCT8 and MCT10, and show that T1AM displays differential inhibition of T3 and T4 cellular uptake by these transporters. T1AM inhibits T3 and T4 transport by OATP1A2 with IC50 values of 0.27 and 2.1 μM, respectively. T4 transport by OATP1C1, which is thought to play a key role in thyroid Hormone transport across the blood-brain barrier, is inhibited by T1AM with an IC50 of 4.8 μM. T1AM also inhibits both T3 and T4 uptake via MCT8, the most specific thyroid Hormone transporter identified to date, with IC50 values of 95 and 31 μM, respectively. By contrast, T1AM has no effect on thyroid Hormone transport by OATP1B3 and MCT10. Given that OATP1A2, OATP1C1, and MCT8 are all present in the brain, T1AM may play an important role in modulating thyroid Hormone delivery and activity in specific target regions in the central nervous system.
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3-Iodothyronamine (T1AM): a new chapter of thyroid Hormone endocrinology?
Molecular BioSystems, 2010Co-Authors: Alexandra G Ianculescu, Thomas S ScanlanAbstract:3-Iodothyronamine (T1AM) is an endogenous thyroid Hormone Derivative with distinct biological effects that are largely opposite those of thyroid Hormone. Administration of T1AM to rodents results in rapid and profound reduction in body temperature, heart rate, and metabolism. The structural similarities between thyroxine, T1AM, and monoamine neurotransmitters suggest an intriguing role for T1AM as both a neuromodulator and a Hormone-like molecule that may constitute a part of thyroid Hormone action. Several recent studies into its molecular mechanisms of action have shown that T1AM can target extracellular receptors such as the trace amine-associated receptors and the α2A adrenergic receptor, modulate the membrane transport of neurotransmitters, and serve as a substrate of specific membrane transport cellular uptake machinery. This review discusses recent T1AM studies, focusing on both the observed in vivo effects of T1AM administration and its actions at the molecular level.
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3-Iodothyronamine (T1AM): A New Player on the Thyroid Endocrine Team?
Endocrinology, 2008Co-Authors: Thomas S ScanlanAbstract:3-Iodothyronamine (T1AM) is an endogenous compound with chemical features that are similar to thyroid Hormone. T1AM has a carbon skeleton identical to that of T4 and contains a single carbon-iodine bond. Theoretically, T1AM could be produced from T4 by enzymatic decarboxylation and deiodination. Recent studies show that T1AM and higher iodinated thyronamines are subject to similar metabolic processing as iodothyronines such as T4, suggesting a biological linkage between iodothyronines and iodothyronamines. In addition, single doses of T1AM administered to rodents induce a hypometabolic state that in certain ways resembles hibernation and is opposite to the effects of excess T4. This review will discuss the latest developments on this recently discovered thyroid Hormone Derivative.
Antonia Lanni - One of the best experts on this subject based on the ideXlab platform.
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Both 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine Prevent Short-term Hepatic Lipid Accumulation via Distinct Mechanisms in Rats Being Fed a High-Fat Diet
Frontiers in Physiology, 2017Co-Authors: Rosalba Senese, Assunta Lombardi, Fernando Goglia, Pieter De Lange, Cristina Leanza, Liliana F. Iannucci, Elena Silvestri, Maria João Moreno, Federica Cioffi, Antonia LanniAbstract:3,3’,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism but it also increases lipogenesis, which at first glance appears contradictory. Recent studies have shown that 3,5-diiodothyronine (T2), a natural thyroid Hormone Derivative, also has the capacity to stimulate hepatic lipid catabolism, however, little is known about its possible effects on lipogenic gene expression. Because genes classically involved in hepatic lipogenesis such as SPOT14, acetyl-CoA-carboxylase (ACC), and fatty acid synthase (FAS) contain thyroid Hormone response elements (TREs), we studied their transcriptional regulation, focusing on TRE-mediated effects of T3 compared to T2 in rats receiving high-fat diet (HFD) for one week. HFD rats showed a marked lipid accumulation in the liver, which was significantly reduced upon simultaneous administration of either T3 or T2 with the diet. When administered to HFD rats, T2, in contrast with T3, markedly downregulated the expression of the above-mentioned genes. T2 downregulated expression of the transcription factors carbohydrate-response element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) involved in activation of transcription of these genes, which explains the suppressed expression of their target genes involved in lipogenesis. T3, however, did not repress expression of the TRE-containing ChREBP gene but repressed SREBP-1c expression. Despite suppression of SREBP-1c expression by T3 (which can be explained by the presence of nTRE in its promoter), the target genes were not suppressed, but normalized to HFD reference levels or even upregulated (ACC), partly due to the presence of TREs on the promoters of these genes and partly to the lack of suppression of ChREBP. Thus, T2 and T3 probably act by different molecular mechanisms to achieve inhibition of hepatic lipid accumulation.
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Both 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine Prevent Short-term Hepatic Lipid Accumulation via Distinct Mechanisms in Rats Being Fed a High-Fat Diet
Frontiers Media S.A., 2017Co-Authors: Rosalba Senese, Assunta Lombardi, Fernando Goglia, Pieter De Lange, Cristina Leanza, Liliana F. Iannucci, Elena Silvestri, Federica Cioffi, Maria Moreno, Antonia LanniAbstract:3,3′,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism but it also increases lipogenesis, which at first glance appears contradictory. Recent studies have shown that 3,5-diiodothyronine (T2), a natural thyroid Hormone Derivative, also has the capacity to stimulate hepatic lipid catabolism, however, little is known about its possible effects on lipogenic gene expression. Because genes classically involved in hepatic lipogenesis such as SPOT14, acetyl-CoA-carboxylase (ACC), and fatty acid synthase (FAS) contain thyroid Hormone response elements (TREs), we studied their transcriptional regulation, focusing on TRE-mediated effects of T3 compared to T2 in rats receiving high-fat diet (HFD) for 1 week. HFD rats showed a marked lipid accumulation in the liver, which was significantly reduced upon simultaneous administration of either T3 or T2 with the diet. When administered to HFD rats, T2, in contrast with T3, markedly downregulated the expression of the above-mentioned genes. T2 downregulated expression of the transcription factors carbohydrate-response element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) involved in activation of transcription of these genes, which explains the suppressed expression of their target genes involved in lipogenesis. T3, however, did not repress expression of the TRE-containing ChREBP gene but repressed SREBP-1c expression. Despite suppression of SREBP-1c expression by T3 (which can be explained by the presence of nTRE in its promoter), the target genes were not suppressed, but normalized to HFD reference levels or even upregulated (ACC), partly due to the presence of TREs on the promoters of these genes and partly to the lack of suppression of ChREBP. Thus, T2 and T3 probably act by different molecular mechanisms to achieve inhibition of hepatic lipid accumulation
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3,5-Diiodo-L-thyronine activates brown adipose tissue thermogenesis in hypothyroid rats.
PLOS ONE, 2015Co-Authors: Assunta Lombardi, Rosalba Senese, Rita De Matteis, Rosa Anna Busiello, Fernando Goglia, Federica Cioffi, Antonia LanniAbstract:3,5-diiodo-l-thyronine (T2), a thyroid Hormone Derivative, is capable of increasing energy expenditure, as well as preventing high fat diet-induced overweight and related metabolic dysfunction. Most studies to date on T2 have been carried out on liver and skeletal muscle. Considering the role of brown adipose tissue (BAT) in energy and metabolic homeostasis, we explored whether T2 could activate BAT thermogenesis. Using euthyroid, hypothyroid, and T2-treated hypothyroid rats (all maintained at thermoneutrality) in morphological and functional studies, we found that hypothyroidism suppresses the maximal oxidative capacity of BAT and thermogenesis, as revealed by reduced mitochondrial content and respiration, enlarged cells and lipid droplets, and increased number of unilocular cells within the tissue. In vivo administration of T2 to hypothyroid rats activated BAT thermogenesis and increased the sympathetic innervation and vascularization of tissue. Likewise, T2 increased BAT oxidative capacity in vitro when added to BAT homogenates from hypothyroid rats. In vivo administration of T2 to hypothyroid rats enhanced mitochondrial respiration. Moreover, UCP1 seems to be a molecular determinant underlying the effect of T2 on mitochondrial thermogenesis. In fact, inhibition of mitochondrial respiration by GDP and its reactivation by fatty acids were greater in mitochondria from T2-treated hypothyroid rats than untreated hypothyroid rats. In vivo administration of T2 led to an increase in PGC-1α protein levels in nuclei (transient) and mitochondria (longer lasting), suggesting a coordinate effect of T2 in these organelles that ultimately promotes net activation of mitochondrial biogenesis and BAT thermogenesis. The effect of T2 on PGC-1α is similar to that elicited by triiodothyronine. As a whole, the data reported here indicate T2 is a thyroid Hormone Derivative able to activate BAT thermogenesis.
Heike Biebermann - One of the best experts on this subject based on the ideXlab platform.
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the trace amine associated receptor 1 agonist 3 iodothyronamine induces biased signaling at the serotonin 1b receptor
Frontiers in Pharmacology, 2018Co-Authors: Julia Braunig, Juliane Dinter, Jens Mittag, Carolin S Hofig, Sarah Paisdzior, Mark Rosowski, Gunnar Kleinau, Michal Szczepek, Patrick Scheerer, Heike BiebermannAbstract:Trace amine-associated receptors (TAARs) belong to the class A G-protein-coupled receptors (GPCR) and are evolutionary related to aminergic receptors. TAARs have been identified to mediate effects of trace amines. TAAR1 signaling is mainly mediated via activation of the Gs/adenylyl cyclase pathway. In addition to classical trace amines, TAAR1 can also be activated by the thyroid Hormone Derivative 3-iodothyronamine (3-T1AM). Pharmacological doses of 3-T1AM induced metabolic and anapyrexic effects, which might be centrally mediated in the hypothalamus in rodents. However, the observed anapyrexic effect of 3-T1AM persists in Taar1 knock-out mice which raises the question whether further GPCRs are potential targets for 3-T1AM and mediate the observed physiological effect. Anapyrexia has been observed to be related to action on aminergic receptors such as the serotonin receptor 1b (5-HT1b). This receptor primarily activates the Gi/o mediated pathway and PLC signaling through the Gof Gi/o. Since the expression profiles of TAAR1 and 5-HT1b overlap, we questioned whether 3-T1AM may activate 5-HT1b. Finally, we also evaluated heteromerization between these two GPCRs and tested signaling under co-expressed conditions. In this study, we showed, that 3-T1AM can induce Gi/o signaling through 5-HT1b in a concentration of 10 µM. Strikingly, at 5-HT1b the ligand 3-T1AM only activates the Gi/o mediated reduction of cAMP accumulation, but not PLC activation. Co-stimulation of 5-HT1b by both ligands did not lead to additive or synergistic signaling effects. In addition, we confirmed the capacity for heteromerization between TAAR1 and 5-HT1b. Under co-expression of TAAR1 and HTR1b, 3-T1AM action is only mediated via TAAR1 and activation of 5-HT1b is abrogated. In conclusion, we found evidence for 5-HT1b as a new receptor target for 3-T1AM, albeit with a different signaling effect than the endogenous ligand. Altogether, this indicates a complex interrelation of signaling effects between the investigated GPCRs and respective ligands.
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DataSheet1.docx
2018Co-Authors: Julia Braunig, Juliane Dinter, Jens Mittag, Carolin S Hofig, Sarah Paisdzior, Mark Rosowski, Gunnar Kleinau, Michal Szczepek, Patrick Scheerer, Heike BiebermannAbstract:Trace amine-associated receptors (TAARs) belong to the class A G-protein-coupled receptors (GPCR) and are evolutionary related to aminergic receptors. TAARs have been identified to mediate effects of trace amines. TAAR1 signaling is mainly mediated via activation of the Gs/adenylyl cyclase pathway. In addition to classical trace amines, TAAR1 can also be activated by the thyroid Hormone Derivative 3-iodothyronamine (3-T1AM). Pharmacological doses of 3-T1AM induced metabolic and anapyrexic effects, which might be centrally mediated in the hypothalamus in rodents. However, the observed anapyrexic effect of 3-T1AM persists in Taar1 knock-out mice which raises the question whether further GPCRs are potential targets for 3-T1AM and mediate the observed physiological effect. Anapyrexia has been observed to be related to action on aminergic receptors such as the serotonin receptor 1b (5-HT1b). This receptor primarily activates the Gi/o mediated pathway and PLC signaling through the Gβγ of Gi/o. Since the expression profiles of TAAR1 and 5-HT1b overlap, we questioned whether 3-T1AM may activate 5-HT1b. Finally, we also evaluated heteromerization between these two GPCRs and tested signaling under co-expressed conditions. In this study, we showed, that 3-T1AM can induce Gi/o signaling through 5-HT1b in a concentration of 10 μM. Strikingly, at 5-HT1b the ligand 3-T1AM only activates the Gi/o mediated reduction of cAMP accumulation, but not PLC activation. Co-stimulation of 5-HT1b by both ligands did not lead to additive or synergistic signaling effects. In addition, we confirmed the capacity for heteromerization between TAAR1 and 5-HT1b. Under co-expression of TAAR1 and HTR1b, 3-T1AM action is only mediated via TAAR1 and activation of 5-HT1b is abrogated. In conclusion, we found evidence for 5-HT1b as a new receptor target for 3-T1AM, albeit with a different signaling effect than the endogenous ligand. Altogether, this indicates a complex interrelation of signaling effects between the investigated GPCRs and respective ligands.
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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.
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Evolutionary Conservation of 3-Iodothyronamine as an Agonist at the Trace Amine-Associated Receptor 1.
European thyroid journal, 2015Co-Authors: Maxi Cöster, Torsten Schöneberg, Heike Biebermann, Claudia StaubertAbstract:The trace amine-associated receptor 1 (Taar1) is a Gs protein-coupled receptor activated by trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T1AM). T1AM is an endogenous biogenic amine and thyroid Hormone Derivative that exerts several biological functions. However, the physiological relevance of T1AM acting via Taar1 is still under discussion. Therefore, we studied the structural and functional evolution of Taar1 in vertebrates to provide evidence for a conserved Taar1-mediated T1AM function. We searched public sequence databases to retrieve Taar1 sequence information from vertebrates. We cloned and functionally characterized Taar1 from selected vertebrate species using cAMP assays to determine the evolutionary conservation of T1AM action at Taar1. We found intact open reading frames of Taar1 in more than 100 vertebrate species, including mammals, sauropsids and amphibians. Evolutionary conservation analyses of Taar1 protein sequences revealed a high variation in amino acid residues proposed to be involved in agonist binding, especially in rodent Taar1 orthologs. Functional characterization showed that T1AM, β-PEA and p-tyramine (p-Tyr) act as agonists at all tested orthologs, but EC50 values of T1AM at rat Taar1 differed significantly when compared to all other tested vertebrate Taar1. The high structural conservation of Taar1 throughout vertebrate evolution highlights the physiological relevance of Taar1, but species-specific differences in T1AM potency at Taar1 orthologs suggest a specialization of rat Taar1 for T1AM recognition. In contrast, β-PEA and p-Tyr potencies were rather conserved throughout all tested Taar1 orthologs. We provide evidence that the observed differences in potency are related to differences in constraint during Taar1 evolution.
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Evolutionary Conservation of 3-Iodothyronamine as an Agonist at the Trace Amine-Associated Receptor 1
European Thyroid Journal, 2015Co-Authors: Maxi Cöster, Torsten Schöneberg, Heike Biebermann, Claudia StaubertAbstract:Objectives: The trace amine-associated receptor 1 (Taar1) is a Gs protein-coupled receptor activated by trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T1AM). T1AM is an endogenous biogenic amine and thyroid Hormone Derivative that exerts several biological functions. However, the physiological relevance of T1AM acting via Taar1 is still under discussion. Therefore, we studied the structural and functional evolution of Taar1 in vertebrates to provide evidence for a conserved Taar1-mediated T1AM function. Study Design: We searched public sequence databases to retrieve Taar1 sequence information from vertebrates. We cloned and functionally characterized Taar1 from selected vertebrate species using cAMP assays to determine the evolutionary conservation of T1AM action at Taar1. Results: We found intact open reading frames of Taar1 in more than 100 vertebrate species, including mammals, sauropsids and amphibians. Evolutionary conservation analyses of Taar1 protein sequences revealed a high variation in amino acid residues proposed to be involved in agonist binding, especially in rodent Taar1 orthologs. Functional characterization showed that T1AM, β-PEA and p-tyramine (p-Tyr) act as agonists at all tested orthologs, but EC50 values of T1AM at rat Taar1 differed significantly when compared to all other tested vertebrate Taar1. Conclusions: The high structural conservation of Taar1 throughout vertebrate evolution highlights the physiological relevance of Taar1, but species-specific differences in T1AM potency at Taar1 orthologs suggest a specialization of rat Taar1 for T1AM recognition. In contrast, β-PEA and p-Tyr potencies were rather conserved throughout all tested Taar1 orthologs. We provide evidence that the observed differences in potency are related to differences in constraint during Taar1 evolution.
Assunta Lombardi - One of the best experts on this subject based on the ideXlab platform.
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Effect of Iodothyronines on Thermogenesis: Focus on Brown Adipose Tissue.
Frontiers in Endocrinology, 2018Co-Authors: Federica Cioffi, Elena Silvestri, Fernando Goglia, Alessandra Gentile, Assunta LombardiAbstract:Thyroid Hormones (THs) significantly influence energy expenditure by affecting the activity of metabolic active tissues, among which mammalian brown adipose tissue (BAT) plays a significant role. For long time, the modulation of BAT activity by 3,3’,5-triiodo-L-thyronine (T3) has been ascribed to its direct actions on this tissue; however, recent evidence indicates that T3, by stimulating specific brain centers, activates the metabolism of BAT via the sympathetic nervous system. These distinct mechanisms of action are not mutually exclusive. New evidence indicates that 3,5-diiodo-L-thyronine (3,5-T2), a thyroid Hormone Derivative, exerts thermogenic effects, by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle and BAT. At the moment, due to the absence of experiments finalized to render a clear cut discrimination between peripheral and central effects induced by 3,5-T2, it is not possible to exclude that some of the metabolic effects exerted by 3,5-T2 may be mediated centrally. Despite this, some evidence suggests that 3,5-T2 plays a role in adrenergic stimulation of thermogenesis in BAT. This mini-review provides an overview of the effects induced by T3 and 3,5-T2 on BAT thermogenesis, with a focus on data suggesting the involvement of central adrenergic stimulation. These aspects may reveal new perspectives in thyroid physiology and in the control of energy metabolism.
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Both 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine Prevent Short-term Hepatic Lipid Accumulation via Distinct Mechanisms in Rats Being Fed a High-Fat Diet
Frontiers in Physiology, 2017Co-Authors: Rosalba Senese, Assunta Lombardi, Fernando Goglia, Pieter De Lange, Cristina Leanza, Liliana F. Iannucci, Elena Silvestri, Maria João Moreno, Federica Cioffi, Antonia LanniAbstract:3,3’,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism but it also increases lipogenesis, which at first glance appears contradictory. Recent studies have shown that 3,5-diiodothyronine (T2), a natural thyroid Hormone Derivative, also has the capacity to stimulate hepatic lipid catabolism, however, little is known about its possible effects on lipogenic gene expression. Because genes classically involved in hepatic lipogenesis such as SPOT14, acetyl-CoA-carboxylase (ACC), and fatty acid synthase (FAS) contain thyroid Hormone response elements (TREs), we studied their transcriptional regulation, focusing on TRE-mediated effects of T3 compared to T2 in rats receiving high-fat diet (HFD) for one week. HFD rats showed a marked lipid accumulation in the liver, which was significantly reduced upon simultaneous administration of either T3 or T2 with the diet. When administered to HFD rats, T2, in contrast with T3, markedly downregulated the expression of the above-mentioned genes. T2 downregulated expression of the transcription factors carbohydrate-response element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) involved in activation of transcription of these genes, which explains the suppressed expression of their target genes involved in lipogenesis. T3, however, did not repress expression of the TRE-containing ChREBP gene but repressed SREBP-1c expression. Despite suppression of SREBP-1c expression by T3 (which can be explained by the presence of nTRE in its promoter), the target genes were not suppressed, but normalized to HFD reference levels or even upregulated (ACC), partly due to the presence of TREs on the promoters of these genes and partly to the lack of suppression of ChREBP. Thus, T2 and T3 probably act by different molecular mechanisms to achieve inhibition of hepatic lipid accumulation.
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Both 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine Prevent Short-term Hepatic Lipid Accumulation via Distinct Mechanisms in Rats Being Fed a High-Fat Diet
Frontiers Media S.A., 2017Co-Authors: Rosalba Senese, Assunta Lombardi, Fernando Goglia, Pieter De Lange, Cristina Leanza, Liliana F. Iannucci, Elena Silvestri, Federica Cioffi, Maria Moreno, Antonia LanniAbstract:3,3′,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism but it also increases lipogenesis, which at first glance appears contradictory. Recent studies have shown that 3,5-diiodothyronine (T2), a natural thyroid Hormone Derivative, also has the capacity to stimulate hepatic lipid catabolism, however, little is known about its possible effects on lipogenic gene expression. Because genes classically involved in hepatic lipogenesis such as SPOT14, acetyl-CoA-carboxylase (ACC), and fatty acid synthase (FAS) contain thyroid Hormone response elements (TREs), we studied their transcriptional regulation, focusing on TRE-mediated effects of T3 compared to T2 in rats receiving high-fat diet (HFD) for 1 week. HFD rats showed a marked lipid accumulation in the liver, which was significantly reduced upon simultaneous administration of either T3 or T2 with the diet. When administered to HFD rats, T2, in contrast with T3, markedly downregulated the expression of the above-mentioned genes. T2 downregulated expression of the transcription factors carbohydrate-response element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) involved in activation of transcription of these genes, which explains the suppressed expression of their target genes involved in lipogenesis. T3, however, did not repress expression of the TRE-containing ChREBP gene but repressed SREBP-1c expression. Despite suppression of SREBP-1c expression by T3 (which can be explained by the presence of nTRE in its promoter), the target genes were not suppressed, but normalized to HFD reference levels or even upregulated (ACC), partly due to the presence of TREs on the promoters of these genes and partly to the lack of suppression of ChREBP. Thus, T2 and T3 probably act by different molecular mechanisms to achieve inhibition of hepatic lipid accumulation
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3,5-Diiodo-L-thyronine activates brown adipose tissue thermogenesis in hypothyroid rats.
PLOS ONE, 2015Co-Authors: Assunta Lombardi, Rosalba Senese, Rita De Matteis, Rosa Anna Busiello, Fernando Goglia, Federica Cioffi, Antonia LanniAbstract:3,5-diiodo-l-thyronine (T2), a thyroid Hormone Derivative, is capable of increasing energy expenditure, as well as preventing high fat diet-induced overweight and related metabolic dysfunction. Most studies to date on T2 have been carried out on liver and skeletal muscle. Considering the role of brown adipose tissue (BAT) in energy and metabolic homeostasis, we explored whether T2 could activate BAT thermogenesis. Using euthyroid, hypothyroid, and T2-treated hypothyroid rats (all maintained at thermoneutrality) in morphological and functional studies, we found that hypothyroidism suppresses the maximal oxidative capacity of BAT and thermogenesis, as revealed by reduced mitochondrial content and respiration, enlarged cells and lipid droplets, and increased number of unilocular cells within the tissue. In vivo administration of T2 to hypothyroid rats activated BAT thermogenesis and increased the sympathetic innervation and vascularization of tissue. Likewise, T2 increased BAT oxidative capacity in vitro when added to BAT homogenates from hypothyroid rats. In vivo administration of T2 to hypothyroid rats enhanced mitochondrial respiration. Moreover, UCP1 seems to be a molecular determinant underlying the effect of T2 on mitochondrial thermogenesis. In fact, inhibition of mitochondrial respiration by GDP and its reactivation by fatty acids were greater in mitochondria from T2-treated hypothyroid rats than untreated hypothyroid rats. In vivo administration of T2 led to an increase in PGC-1α protein levels in nuclei (transient) and mitochondria (longer lasting), suggesting a coordinate effect of T2 in these organelles that ultimately promotes net activation of mitochondrial biogenesis and BAT thermogenesis. The effect of T2 on PGC-1α is similar to that elicited by triiodothyronine. As a whole, the data reported here indicate T2 is a thyroid Hormone Derivative able to activate BAT thermogenesis.