@phdthesis{Pietzner2017,
  author    = {Maik Pietzner},
  title     = {Comprehensive metabolic characterization of thyroid hormone action on human metabolism in population-based and experimental studies},
  journal    = {Umfassende metabolische Charakterisierung der Wirkung von Schilddr{\"u}senhormonen auf den menschlichen Organismus auf Basis von populationsbasierten und experimentellen Studien},
  url       = {https://nbn-resolving.org/urn:nbn:de:gbv:9-002781-1},
  year      = {2017},
  abstract  = {The thyroid gland is of crucial importance in human metabolism. Its main secretion products, L-thyroxine (T4) and 3,3’,5-triiodo-L-thyronine (T3), are essential for proper development of multiple tissues and organs as well as for their functioning in the adult organism. The secretion of thyroid hormones (TH) is stimulated by thyrotropin (TSH) released from the pituitary gland. This tight connection between both hormones is of crucial importance for the clinical diagnosis of thyroid dysfunction. During the last two decades the concept of TH action developed to increased complexity. However, most of the recent advances in the field of TH research are based either on cell culture, tissue or animal models or stem from studies investigating specific hypotheses in humans. Thus, experimental approaches for the comprehensive, hypothesis-free characterization of metabolic effects of classical and non-classical TH in human are urgently needed. This holds true in particular for the TH derivative 3,5-diiodothyronine (3,5-T2). It was described to alleviate the typical detrimental metabolic consequences of a high-fat diet and even reversed hepatic steatosis. To replicate these experimental findings from rodents in humans, comprehensive data from the population-based Study of Health in Pomerania (SHIP) was analyzed in the present work. Based on a euthyroid, diabetes-free SHIP-subsample (N=761), non-linear associations between the serum concentrations of 3,5-T2 and glucose as well as TSH were detected. In contrast, no significant 3,5-T2 associations with several anthropometric markers or blood lipid parameters were observed, partially questioning the transferability of the beneficial metabolic 3,5-T2 effects reported for pharmacological intervention studies on rodents to humans. Recent advances in technological development now allow for the use of high-throughput spectrometric platforms to characterize the small molecule content (metabolome) of blood and urine samples. The detected metabolome constituents can be associated with any relevant parameters of interest, thereby extending the scope of classical association studies. Therefore, in the second part of the present thesis, the metabolic fingerprints of FT4, TSH as well as the ratio log(TSH)/FT4 as markers of thyroid function were profiled. Strong differences between the metabolic fingerprints of FT4 and TSH were observed, partially alleviated by the log(TSH)/FT4 ratio. These findings not only emphasize the high diagnostic value of the combined evaluation of TSH and FT4 in the assessment of thyroid function but additionally argue for a holistic approach in the diagnosis of thyroid function. More moderate endogenous effects of 3,5-T2 were evaluated by comparing its urinary metabolic fingerprint with that of the classical TH. A number of associations became apparent, indicating a function of endogenous 3,5-T2 in intermediary metabolism. Besides partially confirming associations with respect to the presented findings in animal studies, the strongest 3,5-T2-association was observed with trigonelline, a metabolite described earlier to exhibit similar beneficial effects as 3,5-T2 on glucose metabolism when used as a pharmacological agent in animal studies. An association towards hippurate indicated a partial overlap with the metabolic profile of TSH and hence consolidated results from the first two projects in the sense of a thyromimetic role of 3,5-T2 in the feedback regulation of TH. The diagnosis of thyroid disorders based on the classical markers TSH and FT4 suffers from restricted sensitivity in the subclinical range as both parameters have broad reference ranges in the general population. Therefore, in an approach to detect novel peripheral biomarkers of thyroid function, sixteen healthy young men were challenged with 250 µg of levothyroxine (L-T4) over a period of eight weeks in the fourth project presented here as part of this thesis. Monitoring of the volunteers over a period of sixteen weeks allowed delineation of the metabolic shifts first towards thyrotoxicosis and later in the context of the restoration of euthyroidism. The use of mass spectrometry for the comprehensive characterization of the metabolite as well as the protein content of samples taken at the different time points revealed profound molecular alterations, despite the lack of any clinical symptoms in the volunteers. Molecular signatures of thyrotoxicosis indicated increased energy expenditure, pronounced defense against systemic oxidative stress, a general drop in apolipoproteins, as well as increased abundances of proteins related to the coagulation cascade and the complement system. Good and robust classification of the thyroid state independent of TSH and FT4 was achieved using random forest analysis with a subset of fifteen metabolites and proteins, indicating new options in the individualized diagnosis of thyroid disorders.},
  language  = {en}
}