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

甲状腺激素(TH)及其代谢产物是能量代谢的关键调节因子。相反，限制能量和减肥会改变他们的新陈代谢。甲状腺拟态活性的T_3通过与核T_3受体结合来调节其大部分作用。天然的T3代谢物3，5-T2增加脂肪代谢，没有心脏毒性副作用。一种新的脱羧基TH代谢物，3-T1-胺(3-T1AM)，在药物浓度下对食物摄入量产生剂量依赖效应，将碳水化合物转化为脂肪代谢，降低体温和心脏参数。与G蛋白偶联的微量胺相关受体介导了这些效应。TH轴的组成部分在下丘脑对促甲状腺激素释放激素神经元等促食欲途径的调节中起着至关重要的作用。最近，我们发现TAMs是人类脱碘酶的真正底物，它以细胞特异性的方式代谢TH，现在发现肥胖青少年血液中3-T1AM水平降低。因此，我们假设，生热(T3，3，5-T2)和“降温”(3-T1AM)代谢物导致了肥胖患者能量消耗和体重增加之间的失衡。我们期望通过更好地了解新的TH代谢物的生理作用以及这些化合物在瘦素和/或Ghrelin拮抗剂辅助的小鼠模型中的药理应用，可以改变体重恢复。在本项目中，我们将1)分析TH及其代谢物在体重增加/减轻/体重恢复-维持期间的变化；2)测试新型TH代谢物能否预防实验性小鼠模型的体重恢复；3)确定在体重恢复/体重保持期间参与TH轴调节的外周成分的组织特异性贡献和适应性；4)表征选定的TH及其代谢物及其类似物在具有代表性的靶细胞(肝脏、肌肉、白色脂肪组织)中的作用机制。我们希望对TH和的作用机制有进一步的了解，TH的新代谢物将被证明是有用的诊断工具或药物治疗策略。

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.