Novel physiological thyroid hormone metabolites as potent modulators of energy expenditure and body weight

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Thyroid hormones (TH) and their metabolites are key regulators of energy metabolism. Conversely, energy restriction and weight loss alter their metabolism. The thyromimetically active T3 mediates most of its action via binding to nuclear T3 receptors. The natural T3 metabolite 3,5-T2 increases lipid metabolism without cardiotoxic side effects. A novel decarboxylated TH metabolite, 3-T1-amine (3-T1AM), exerts dose-dependent effects on food intake, shifts carbohydrate to lipid metabolism, decreases body temperature, and cardiac parameters at pharmacological concentrations. Trace amine-associated receptors, coupled to G-proteins mediate these effects. Components of the TH axis are critically involved in hypothalamic regulation of orexigenic pathways such as thyrotropin releasing-hormone neurons. Recently, we identified TAMs as bona fide substrates of human deiodinase enzymes, which metabolize TH in a cell specific manner and now find decreased 3-T1AM levels in the blood of obese adolescents. Therefore, we hypothesize that thermogenic (T3, 3,5-T2) vs. “cooling” (3-T1AM) TH metabolites contributes to the dysbalance between energy expenditure and weight gain in obesity. We expect that weight regain can be modified by a better understanding of the physiological roles of novel TH metabolites and the pharmacological application of such compounds in mouse models adjuvant to leptin and/or ghrelin antagonists. In this project we will 1) analyze TH and TAM profiles during weight gain/weight reduction/weight regain-maintenance, 2) test whether weight regain can be prevented by novel TH metabolites in experimental mouse models, 3) determine the tissuespecific contribution and adaptations of peripheral components involved in regulation of the TH axis during weight regain/weight maintenance, 4) characterize selected TH, their metabolites and analogs with respect to their mechanism of action in representative target cells (liver, muscle, white adipose tissue). We expect further insight into mechanisms of TH and TAM action and that novel metabolites of TH will prove useful either as diagnostic tools or pharmacological treatment strategies.