Abstract
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.
Highlights
The classical thyroid hormones (TH) thyroxine (T4) and triiodothyronine (T3) represent key regulators of development and metabolic homeostasis [1]
It was reported that 3,5-T2 exerts these effects independent of classical TH-signaling through nuclear receptors and without the well-known thyrotoxic side effects on bone, heart, and the hypothalamus/pituitary/thyroid (HPT) axis
None of the common thyroid function parameters was significantly associated with [3,5-T2] (Fig. 1) and, [3,5-T2] was unaltered during experimental LT4induced thyrotoxicosis (Fig. 1)
Summary
The classical thyroid hormones (TH) thyroxine (T4) and triiodothyronine (T3) represent key regulators of development and metabolic homeostasis [1]. In particular, more recent animal studies [12,13] challenged this optimistic view by demonstrating adverse consequences of dose-dependent 3,5-T2 treatment such as an increased heart weight and suppression of the HPT-axis [14,15,16,17,18] This confirmed the results of earlier in vivo studies in rats that indicated differential liver stimulating- and thyrotropin (TSH)-suppressing thyromimetic effects of 3,5-T2 compared with T3 [19]. 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.
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