Metabolic Profiling Provides a System Understanding of Hypothyroidism in Rats and Its Application

Abstract

BackgroundHypothyroidism is a chronic condition of endocrine disorder and its precise molecular mechanism remains obscure. In spite of certain efficacy of thyroid hormone replacement therapy in treating hypothyroidism, it often results in other side effects because of its over-replacement, so it is still urgent to discover new modes of treatment for hypothyroidism. Sini decoction (SND) is a well-known formula of Traditional Chinese Medicine (TCM) and is considered as efficient agents against hypothyroidism. However, its holistic effect assessment and mechanistic understanding are still lacking due to its complex components.Methodology/Principal FindingsA urinary metabonomic method based on ultra performance liquid chromatography coupled to mass spectrometry was employed to explore global metabolic characters of hypothyroidism. Three typical hypothyroidism models (methimazole-, propylthiouracil- and thyroidectomy-induced hypothyroidism) were applied to elucidate the molecular mechanism of hypothyroidism. 17, 21, 19 potential biomarkers were identified with these three hypothyroidism models respectively, primarily involved in energy metabolism, amino acid metabolism, sphingolipid metabolism and purine metabolism. In order to avert the interference of drug interaction between the antithyroid drugs and SND, the thyroidectomy-induced hypothyroidism model was further used to systematically assess the therapeutic efficacy of SND on hypothyroidism. A time-dependent recovery tendency was observed in SND-treated group from the beginning of model to the end of treatment, suggesting that SND exerted a recovery effect on hypothyroidism in a time-dependent manner through partially regulating the perturbed metabolic pathways.Conclusions/SignificanceOur results showed that the metabonomic approach is instrumental to understand the pathophysiology of hypothyroidism and offers a valuable tool for systematically studying the therapeutic effects of SND on hypothyroidism.

Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

“…As discussed below, our results regarding trigonelline, pyroglutamate or acetone support and extend previously observed associations between 3,5-T 2 and glucose or lipid metabolism as demonstrated by various animal models [4,5,8,25,26,27,28,29]. Furthermore, we observed thyromimetic, but TSH independent, associations regarding hippurate and pyroglutamate, as observed in recent animal studies [17,19]. …”

“…In concordance with this hypothesis, we observed an association with urine levels of hippurate, which were shown to be elevated in the case of experimental induction of hypothyroidism in rats [19]. Since previous work [12] suggested unaltered serum 3,5-T 2 concentrations in hypothyroidism, a decreased ratio of the putative precursor T 4 (T 3 ) and 3,5-T 2 could account for this observation.…”

“…Moreover, in the present study the inclusion of subjects with abnormal serum 3,5-T 2 or TSH concentrations led to weaker associations, suggesting differing roles of serum 3,5-T 2 on intermediary metabolism in different thyroid states. It is worth noting that, besides hippurate, 3,5-T 2 exhibited a unique associated urinary metabolic profile in comparison with TSH and fT 4 [19]. …”

“…Urine, which is readily available, as a downstream product of human metabolism can especially mirror the impact of genetic determinants, environmental factors, personal behavior, nutrition and therapeutic intervention [16]. Despite these advantages, the use of metabolomics in the investigation of TH (metabolite) action is, to the best of our knowledge, limited to intervention studies in rodents [17,18,19,20,21] and, with the exception of a recent study on the relation between TH status and serum metabolites [22], completely lacking in humans. Therefore, the present study was designed to gain further insights into the metabolic profiles associated with circulating 3,5-T 2 by means of urine metabolomics in a large euthyroid study population.…”

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

“…In particular, only few studies attempted to detect peripheral TH effects by untargeted approaches. The influence of thyroid dysfunction on various tissue-specific proteomes or the metabolomes of serum and urine was assessed almost entirely using rodent models [15–18]. Even if these studies undoubtedly added to our understanding of TH action on metabolism, translation of these results to humans is still missing.…”