Josef Köhrle

On the importance of selenium and iodine metabolism for thyroid hormone biosynthesis and human health.

The trace elements iodine and selenium (Se) are essential for thyroid gland functioning and thyroid hormone biosynthesis and metabolism. While iodine is needed as the eponymous constituent of the two major thyroid hormones triiodo-L-thyronine (T3), and tetraiodo-L-thyronine (T4), Se is essential for the biosynthesis and function of a small number of selenocysteine (Sec)-containing selenoproteins implicated in thyroid hormone metabolism and gland function. The Se-dependent iodothyronine deiodinases control thyroid hormone turnover, while both intracellular and secreted Se-dependent glutathione peroxidases are implicated in gland protection. Recently, a number of clinical supplementation trials have indicated positive effects of increasing the Se status of the participants in a variety of pathologies. These findings enforce the notion that many people might profit from improving their Se status, both as a means to reduce the individual health risk as well as to balance a Se deficiency which often develops during the course of illness. Even though the underlying mechanisms are still largely uncharacterised, the effects of Se appear to be exerted via multiple different mechanisms that impact most pronounced on the endocrine and the immune systems.

Welcome to Thyroid Research

Welcome to the first issue of Thyroid Research, a new journal published by BioMed Central, which aims at providing a platform for both researchers and clinicians to discuss a broad spectrum of thyroidology and related issues. These include physiological mechanisms of thyroid hormone action, secretory regulations, immunological and genetic aspects and, finally, news and information on state-of-the-art diagnostic equipment and treatment protocols for more effective management of thyroid disorders.

3-Iodothyronamine reduces insulin secretion in vitro via a mitochondrial mechanism

PURPOSEn3-iodothyronamine (3-T1AM), a decarboxylated and deiodinated thyroid hormone metabolite, leads at pharmacological doses to hypoinsulinemia, hyperglucagonemia and hyperglycemia inxa0vivo. 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).nnnMETHODSnMurine 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.nnnRESULTSnMIN6 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.nnnCONCLUSIONSnThis data provides a first link between cellular 3-T1AM uptake and regulation of mitochondrial energy metabolism in ß-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 inxa0vitro.

Canonical TSH Regulation of Cathepsin-Mediated Thyroglobulin Processing in the Thyroid Gland of Male Mice Requires Taar1 Expression

Trace amine-associated receptor 1 (Taar1) has been suggested as putative receptor of thyronamines. These are aminergic messengers with potential metabolic and neurological effects countering their contingent precursors, the thyroid hormones (THs). Recently, we found Taar1 to be localized at the primary cilia of rodent thyroid epithelial cells in vitro and in situ. Thus, Taar1 is present in a location of thyroid follicles where it might be involved in regulation of cathepsin-mediated proteolytic processing of thyroglobulin, and consequently TH synthesis. In this study, taar1 knock-out male mice (taar1-/-) were used to determine whether Taar1 function would entail differential alterations in thyroid states of young and adult animals. Analyses of blood serum revealed unaltered T4 and T3 concentrations and unaltered T3-over-T4 ratios upon Taar1 deficiency accompanied, however, by elevated TSH concentrations. Interestingly, TSH receptors, typically localized at the basolateral plasma membrane domain of wild type controls, were located at vesicular membranes in thyrocytes of taar1-/- mice. In addition, determination of epithelial extensions in taar1-/- thyroids showed prismatic cells, which might indicate activation states higher than in the wild type. While gross degradation of thyroglobulin was comparable to controls, deregulated thyroglobulin turnover in taar1-/- mice was indicated by luminal accumulation of covalently cross-linked thyroglobulin storage forms. These findings were in line with decreased proteolytic activities of thyroglobulin-solubilizing and -processing proteases, due to upregulated cystatins acting as their endogenous inhibitors in situ. In conclusion, Taar1-deficient mice are hyperthyrotropinemic in the absence of respective signs of primary hypothyroidism such as changes in body weight or TH concentrations in blood serum. Thyrocytes of taar1-/- mice are characterized by non-canonical TSH receptor localization in intracellular compartments, which is accompanied by altered thyroglobulin turnover due to a disbalanced proteolytic network. These finding are of significance considering the rising popularity of using TAAR1 agonists or antagonists as neuromodulating pharmacological drugs. Our study highlights the importance of further evaluating potential off-target effects regarding TSH receptor mislocalization and the thyroglobulin processing machinery, which may not only affect the TH-generating thyroid gland, but may emanate to other TH target organs like the CNS dependent on their proper supply.

Steroidhormone – Produkte von Nebennierenrinde und Keimdrüsen

Steroidhormone bilden eine umfangreiche Gruppe von Hormonen, die sich vom Cholesterin ableiten. Sie werden v. a. in der Nebennierenrinde, den Hoden sowie den Ovarien synthetisiert. Alle Steroidhormone wirken uber nucleare Rezeptoren. Ihr Wirkungsspektrum reicht von der Beeinflussung des Intermediar- und Knochenstoffwechsels bis zur Regulation der mannlichen bzw. weiblichen Sexualentwicklung und -funktion.

Wachstumshormon und Prolactin

In den vorangegangenen Kapiteln wurden die glandotropen Hypophysenhormone besprochen, nun wenden wir uns den Proteohormonen Wachstumshormon (GH, growth hormone) und Prolactin (PRL) zu. GH stimuliert das Korperwachstum, viele anabole und regenerative Vorgange und den Energiestoffwechsel.

Schilddrüsenhormone – Zentrale Regulatoren von Entwicklung, Wachstum, Grundumsatz, Stoffwechsel und Zelldifferenzierung

Die Schilddrusenhormone Thyroxin (T4) und Triiodthyronin (T3) steuern Entwicklung, Wachstum, Zelldifferenzierung, die meisten anabolen und katabolen Stoffwechselwege sowie viele Reaktionen des Struktur- und Funktionsstoffwechsels. Das biologisch aktive Hormon der Schilddruse ist das T3. Es entsteht aus dem als Prohormon dienenden T4 durch enzymatische Deiodierung. Seine Wirkungen werden uberwiegend durch nucleare T3-Rezeptoren (TRα, TRβ) vermittelt, die als ligandenabhangige Transkriptionsfaktoren die Transkription vieler Gene regulieren.

Hormone des Hypothalamus und der Hypophyse

Der Hypothalamus ist mit der Hypophyse uber das Infundibulum verbunden; hieraus ergibt sich eine anatomische und funktionale Einheit, die als ubergeordnetes Zentrum die hierarchisch organisierten Hormonachsen steuert.