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，能量限制和体重减轻会改变他们的新陈代谢。促甲状腺激素活性T3通过与核T3受体结合介导其大部分作用。天然T3代谢产物3，5-T2增加脂质代谢，而没有心脏毒性副作用。一种新的脱羧TH代谢物，3-T1-胺（3-T1 AM），在药理学浓度下对食物摄入量产生剂量依赖性影响，将碳水化合物代谢转变为脂质代谢，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这些作用。TH轴的组成部分是至关重要的下丘脑的食欲调节途径，如促甲状腺激素释放激素神经元。最近，我们确定TAM作为人类脱碘酶的真正底物，以细胞特异性方式代谢TH，现在发现肥胖青少年血液中3-T1 AM水平降低。因此，我们假设产热（T3，3，5-T2）与“冷却”（3-T1 AM）TH代谢物有助于肥胖症中能量消耗和体重增加之间的失衡。我们预计，可以通过更好地理解新的TH代谢物的生理作用和这些化合物在小鼠模型中辅助瘦素和/或生长激素释放肽拮抗剂的药理学应用来修改体重恢复。在该项目中，我们将1）分析体重增加/体重减轻/体重恢复-维持期间的TH和TAM谱，2）在实验小鼠模型中测试新的TH代谢物是否可以预防体重恢复，3）确定在体重恢复/体重维持期间参与TH轴调节的外周组分的组织特异性贡献和适应，4）表征所选TH，它们的代谢物和类似物在代表性靶细胞（肝脏、肌肉、白色脂肪组织）中的作用机制。我们期望进一步深入了解TH和TAM的作用机制，TH的新代谢产物将被证明是有用的，无论是作为诊断工具或药理学治疗策略。

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.