A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans

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.

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…Of special interest was, similar to the previous studies, the lack of a clear association with serum T4 and/or T3 concentrations (44,45). In a follow-up study of the same cohort, 3,5-T2 serum concentrations were analyzed with respect to urine metabolites analyzed by 1 H-NMR spectroscopy (45)(46)(47)(48). Again, very few individuals had remarkably elevated 3,5-T2 serum concentrations that might be suggestive of underlying disease, although health status could not be traced back due to the population-based study using anonymized sera.…”

“…Associations of the 3,5-T2 concentrations with various clinical chemistry parameters were moderate. Of special interest was, similar to the previous studies, the lack of a clear association with serum T4 and/or T3 concentrations (44,45). In a follow-up study of the same cohort, 3,5-T2 serum concentrations were analyzed with respect to urine metabolites analyzed by 1 H-NMR spectroscopy (45)(46)(47)(48).…”

“…This observation is the first one to link a THM to coffee consumption, and so far, no clearcut hypothesis has been tested to challenge a potential causal relationship (45,46). However, indirect evidence might support the assumption that hepatic accumulation of 3,5-T2 (see below) may alter hepatic (and/or renal) metabolism of components consumed with (caffeinated and decaffeinated) coffee and thus even might provide a link between beneficial antisteatotic effects ascribed to 3,5-T2 and also to coffee consumption (44)(45)(46)(47)(48) (Figure 4). Table 2 summarizes the observations made in various pathophysiological states with respect to altered 3,5-T2 concentration in human serum, as determined by the monoclonal antibody-based CLIA.…”

Hepatic Steatosis Is Associated With Adverse Molecular Signatures in Subjects Without Diabetes

“…A detailed description of all applied measurement techniques is given in the Supplemental Information. Briefly, four different approaches were combined: 1) non-targeted MS-based profiling of plasma and urine samples as reported previously [27] 2) targeted MS-based profiling of plasma samples using the AbsoluteIDQ p180 Kit (BIOCRATES LifeSciences AG, Innsbruck, Austria) 3) NMR-based profiling of urine samples as reported previously [28] and 4) NMRbased profiling of plasma samples to derive lipoprotein particles.…”

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

“…In humans, a few studies have confirmed that the administration of 3,5-T2 can increase the resting metabolic rate, also reducing adiposity and body weight without side effects [250]. Interestingly, through molecular fingerprinting experiments, a strong positive association has been found between the 3,5-T2 levels in the human serum and compounds related to coffee consumption [326]. Taken together, all these finding are encouraging and provide evidence that 3,5-T2 might become a therapeutic agent of utmost importance.…”