Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

Abstract

BackgroundDeterminations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model.MethodsA 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 FT4 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.ResultsDespite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-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.ConclusionOur results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, 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 materialThe online version of this article (doi:10.1186/s12916-016-0770-8) contains supplementary material, which is available to authorized users.

A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence

“…The comprehensive evaluation of plasma metabolites has the potential to elucidate biomarkers and metabolomic signatures associated with aging (Fuchs et al 2010 ; Mishur and Rea 2012 ; Tomás-Loba et al 2013 ; Laye et al 2015 ; Hoffman et al 2016 ; Wan et al 2017 ; Pietzner et al 2017 ), lifestyle interventions (dietary restriction/exercise) that prolong good health (De Guzman et al 2013 ; Laye et al 2015 ; Green et al 2017 ; Lewis et al 2010 ), and diseased states such as cancer (Nagrath et al 2011 ), diabetes (Liu et al 2013 ), and cardiovascular disease (Barderas et al 2011 ). As such, metabolomic analyses provide a powerful hypothesis-generating tool for mechanisms that may extend life span.…”

Differences in the Plasma Proteome of Patients with Hypothyroidism before and after Thyroid Hormone Replacement: A Proteomic Analysis

“…Primary hypothyroidism is considered to form one end of this spectrum as Hashimoto’s thyroiditis and is clinically characterized by decreased free thyroxine (T4) and increased TSH circulating levels. Studies have examined additional plasma markers for hypothyroidism by studying the effect of physiological decreases in thyroid hormones (TH) on plasma proteins by utilizing either animal models [ 13 ], cell lines [ 14 ], and more recently in humans with induced hypothyroidism by administering l -thyroxine [ 15 ]. It is well-known that TH regulates plasma protein synthesis and secretion through its actions on target genes and their response elements [ 16 ].…”

Changes in Body Compositions and Basal Metabolic Rates during Treatment of Graves’ Disease

“…Small changes in the dose of levothyroxine or target TSH levels could affect the REE in patients with hypothyroidism [ 15 – 17 ]. In healthy men, the administration of levothyroxine for 8 weeks increased the proteins related with the REE [ 18 ]. In consistent with previous reports [ 2 , 3 ], the present study showed that the antithyroid treatment reduced the increased REE by hyperthyroidism following the increased body weight and compositional changes.…”