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      Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

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          Abstract

          Background

          Determinations of thyrotropin (TSH) and free thyroxine (FT 4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT 4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model.

          Methods

          A sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT 4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure.

          Results

          Despite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT 4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT 4. Main FT 4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels.

          Conclusion

          Our results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT 4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12916-016-0770-8) contains supplementary material, which is available to authorized users.

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          Most cited references93

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Thyroid hormone regulation of metabolism.

            Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
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              Physiological and molecular basis of thyroid hormone action.

              P M Yen (2001)
              Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.
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                Author and article information

                Contributors
                maik.pietzner@uni-greifswald.de
                beatrice.engelmann@uni-greifswald.de
                tim.kacprowski@uni-greifswald.de
                janine.golchert@uni-greifswald.de
                anna-luisedirk@web.de
                hammer@uni-greifswald.de
                alexander.iwen@uksh.de
                matthias.nauck@uni-greifswald.de
                henri.wallaschofski@hotmail.com
                dagmar.fuehrer-sakel@uk-essen.de
                thomas.muente@neuro.uni-luebeck.de
                nele.friedrich@uni-greifswald.de
                voelker@uni-greifswald.de
                +49 (0)3834/86 5873 , georg.homuth@uni-greifswald.de
                georg.brabant@uksh.de
                Journal
                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central (London )
                1741-7015
                9 January 2017
                9 January 2017
                2017
                : 15
                : 6
                Affiliations
                [1 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany
                [2 ]DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
                [3 ]Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 15a, D-17475 Greifswald, Germany
                [4 ]Medical Clinic I, University of Lübeck, Experimental and Clinical Endocrinology, Ratzeburger Allee 160, Zentralklinikum (Haus 40), 23538 Lübeck, Germany
                [5 ]Private Practice Endocrinology, Krämpferstraße 6, 99094 Erfurt, Germany
                [6 ]Department of Endocrinology and Metabolism, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany
                [7 ]Department of Neurology, University of Lübeck, Ratzeburger Allee 169, 23538 Lübeck, Germany
                [8 ]Research Centre for Prevention and Health, Glostrup University Hospital, Nordre Ringvej 57, 2600 Glostrup, Denmark
                [9 ]ZIK-FunGene (Zentrum für Innovationskompetenz - Funktionelle Genomforschung), Greifswald, Germany
                Article
                770
                10.1186/s12916-016-0770-8
                5220622
                28065164
                67d47ef3-539e-4454-8db5-851f445a2ba1
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 September 2016
                : 15 December 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: WA 1328/5-1
                Award ID: MU 3811/16-2
                Award ID: FR 3055/4-1
                Award ID: VO 1444/9-1
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DE)
                Award ID: BR 915/14-1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007601, Horizon 2020;
                Award ID: Marie Skłodowska-Curie Grant Agreement number 657595
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DE)
                Award ID: FU 356/7-1
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Medicine
                hyperthyroidism,metabolomics,proteomics,thyroid function,thyrotoxicosis
                Medicine
                hyperthyroidism, metabolomics, proteomics, thyroid function, thyrotoxicosis

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