Empowering thyroid hormone research in human subjects using OMICs technologies

Pietzner, Maik; Kacprowski, Tim; Friedrich, Nele

doi:10.1530/joe-18-0117

Cited by 18 publications

(15 citation statements)

References 82 publications

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“…Of special interest was, similar to the previous studies, the lack of a clear association with serum T4 and/or T3 concentrations (44,45). In a follow-up study of the same cohort, 3,5-T2 serum concentrations were analyzed with respect to urine metabolites analyzed by 1 H-NMR spectroscopy (45)(46)(47)(48). Again, very few individuals had remarkably elevated 3,5-T2 serum concentrations that might be suggestive of underlying disease, although health status could not be traced back due to the population-based study using anonymized sera.…”

Section: A Chemoluminescence Assay Based On Monoclonal Antibodies Detmentioning

confidence: 73%

“…This observation is the first one to link a THM to coffee consumption, and so far, no clearcut hypothesis has been tested to challenge a potential causal relationship (45,46). However, indirect evidence might support the assumption that hepatic accumulation of 3,5-T2 (see below) may alter hepatic (and/or renal) metabolism of components consumed with (caffeinated and decaffeinated) coffee and thus even might provide a link between beneficial antisteatotic effects ascribed to 3,5-T2 and also to coffee consumption (44)(45)(46)(47)(48) (Figure 4). Table 2 summarizes the observations made in various pathophysiological states with respect to altered 3,5-T2 concentration in human serum, as determined by the monoclonal antibody-based CLIA.…”

Section: A Chemoluminescence Assay Based On Monoclonal Antibodies Detmentioning

confidence: 99%

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3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

et al. 2020

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Structural formula of the "Janus-faced" THM 3,5-diiodo-L-thyronine (left), which has the same 3,5-iodine substitution pattern as its putative precursors L-T4 and L-T3 at the tyrosyl-ring, but lacks the iodine substitution in 3 ′-position of the phenolic ring which is essential for binding classical T3-receptors and conveying canonical and non-canonical thyromimetic effects. The roman god Janus symbolized "duality" and "jani" were ceremonial gateways in ancient Rome typically used for symbolically auspicious entrances or exits. Janus-face (right) source: This image comes from the 4th edition of Meyers Konversationslexikon (1885-90). The copyrights have expired and this image is in the public domain. Wikimedia, Meyers_b9_s0153_b1.png. HYPOTHESES AND THEORY a. 3,5-T2 is an endogenous metabolite of thyroid hormones T4 and T3 b. 3,5-T2 might represent the precursor of 3-iodothyronamine c. 3,5-T2 acts like T3 via canonical activation of T3 receptors albeit with lower potency d. 3,5-T2 exerts actions distinct from those of thyromimetically active T3 i) via mitochondrial targets ii) by its intrahepatic accumulation iii) by its intracrine mode of action e. 3,5-T2 formation and action might be altered in patients on T4 replacement therapy and causes adverse effects if abused.

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Section: A Chemoluminescence Assay Based On Monoclonal Antibodies Detmentioning

confidence: 73%

Section: A Chemoluminescence Assay Based On Monoclonal Antibodies Detmentioning

confidence: 99%

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

et al. 2020

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“…Second, the metabolomic 3,5-T2 fingerprint, especially the main signature of caffeine-related metabolites, was quite different from those described for thyroid diseases or circulating TH (36,43–46). The fingerprint of TH in plasma is dominated by lipid species, γ-glutamyl dipeptides, and shifts in amino acid proportions (47). Merely for the urine metabolome, a small overlap between the fingerprints of 3,5-T2 and classical TH was observed, as hippurate and trigonelline were also associated with the TSH and fT4 serum concentrations, respectively, in population-based studies (43,48).…”

Section: Discussionmentioning

confidence: 99%

A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans

Pietzner

Köhrle

Lehmphul

et al. 2019

Thyroid

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Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiodo-L-thyronine (3,5-T2), a metabolite of the thyroid hormones (TH) thyroxine (T4) and triiodo-L-thyronine (T3), was reported to cause beneficial health effects, including reversal of steatohepatosis and prevention of insulin resistance, in most instances without adverse thyrotoxic side effects. However, the empirical evidence concerning the physiological relevance of endogenously produced 3,5-T2 in humans is comparatively poor. Therefore, to improve the understanding of 3,5-T2-related metabolic processes, we performed a comprehensive metabolomic study relating serum 3,5-T2 concentrations to plasma and urine metabolite levels within a large general population sample.Methods: Serum 3,5-T2 concentrations were determined for 856 participants of the population-based Study of Health in Pomerania-TREND (SHIP-TREND). Plasma and urine metabolome data were generated using mass spectrometry and nuclear magnetic resonance spectroscopy, allowing quantification of 613 and 578 metabolites in plasma and urine, respectively. To detect thyroid function-independent significant 3,5-T2—metabolite associations, linear regression analyses controlling for major confounders, including thyrotropin and free T4, were performed. The same analyses were carried out using a sample of 16 male healthy volunteers treated for 8 weeks with 250 μg/day levothyroxine to induce thyrotoxicosis.Results: The specific molecular fingerprint of 3,5-T2 comprised 15 and 73 significantly associated metabolites in plasma and urine, respectively. Serum 3,5-T2 concentrations were neither associated with classical thyroid function parameters nor altered during experimental thyrotoxicosis. Strikingly, many metabolites related to coffee metabolism, including caffeine and paraxanthine, formed the clearest positively associated molecular signature. Importantly, these associations were replicated in the experimental human thyrotoxicosis model.Conclusion: The molecular fingerprint of 3,5-T2 demonstrates a clear and strong positive association of the serum levels of this TH metabolite with plasma levels of compounds indicating coffee consumption, therefore pointing to the liver as an organ, the metabolism of which is strongly affected by coffee. Furthermore, 3,5-T2 serum concentrations were found not to be directly TH dependent. Considering the beneficial health effects of 3,5-T2 administration observed in animal models and those of coffee consumption demonstrated in large epidemiological studies, one might speculate that coffee-stimulated hepatic 3,5-T2 production or accumulation represents an important molecular link in this connection.

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“…Finally, population-based studies employing other omics, such as transcriptomics, proteomics, and metabolomics, are outside the scope of this review, but they may also lead to new insights in thyroid physiology and pathophysiology, as recently discussed elsewhere (117).…”

Section: Epigenetic Determinants Of Thyroid Function and Other Omics mentioning

confidence: 99%

The Genetic Basis of Thyroid Function: Novel Findings and New Approaches

Kuś

Chaker

Teumer

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels. Evidence Acquisition This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease. Evidence Synthesis Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint. Conclusions Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice.

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Empowering thyroid hormone research in human subjects using OMICs technologies

Cited by 18 publications

References 82 publications

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans

The Genetic Basis of Thyroid Function: Novel Findings and New Approaches

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