Effects of thyronamines (TAM) and thyroacetic acid (TAC) metabolites on energy metabolism, mitochondrial function, Ca2+-signalling, plasma membrane action

甲状腺胺 (TAM) 和甲状腺乙酸 (TAC) 代谢物对能量代谢、线粒体功能、Ca2 信号传导、质膜作用的影响

• 批准号: 221223920
• 负责人: Dr. Georg Homuth
• 金额: --
• 依托单位: Institut für Experimentelle Endokrinologie (CVK)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221223920?language=en
• 关键词: Effects; thyronamines; TAM; thyroacetic; acid

Blood and various tissues contain the classical thyroid hormones (TH), T4 and T3, but also several TH metabolites (THM) with less iodine, modifications of their side chain or phenolic group. Cold decarboxylated thyronamines (TAM), their acetic acid metabolites (TA) generated by amine oxidases and N-acetylated TAM exert distinct, even antagonizing effects compared to hot T3 and its 5-prime-deiodination product 3,5-T2 by different mechanisms of action. During the first funding period we observed that 3-T1AM suppresses gene expression of a specific subset of thyroid-relevant genes, e.g. sodium-iodide-transporter (NIS) and thyreoglobulin (Tg) in rat PCCl3 thyrocytes in vitro and in mice in vivo without altering the pituitary-thyroid axis. Cooperating with Dr. Mergler we discovered rapid activation of plasma membrane transient receptor potential cold channel M8 (TRPM8) by 3-T1AM in various cell types, associated with altered intracellular calcium signaling and inhibition of hot TRPV1 channel activity resulting in altered cellular function. Together with Dr. Höfig we identified ornithine decarboxylase (ODC) as catalyst of 3-T1AM generation from the prohormone T4 and the THM 3,5-T2. Both of these THM, 3,5-T2 and 3-T1AM exert distinct actions on cellular energy metabolism in cell type-specific manner as measured by Seahorse extracellular flux analyser. Aims of the second funding period are (1) characterization of presumably ODC-mediated 3-T1AM biosynthesis, (2) analysis of effects of 3-T1AM, its precursor(s) and metabolite(s) on a) function of the thyroid and b) pancreatic islets, especially glucagon secretion. These aims will be addressed using functional mouse thyroid follicles grown in vitro from embryonic stem cells and primary thyroid cultures as well as glucagon-secreting alpha-cell(s) line(s) and isolated mouse islets. Gene and proteome expression analysis combined with mechanistic and functional studies will enhance our knowledge on biosynthesis and cell-specific action of THM, especially 3-T1AM and thus contribute to a better understanding of (patho)-physiological metabolic signatures of non-classical THM.

血液和各种组织含有经典的甲状腺激素（TH），T4和T3，但也有几种TH代谢物（THM），碘含量较低，其侧链或酚基的修饰。与热T3及其5-prime-deiodination产物3，5-T2相比，冷脱羧甲状腺原氨酸（TAM）及其由胺氧化酶产生的乙酸代谢产物（TA）和N-乙酰化TAM通过不同的作用机制发挥明显的甚至拮抗作用。在第一个资助期内，我们观察到3-T1 AM抑制甲状腺相关基因的特定子集的基因表达，例如大鼠PCCl 3甲状腺细胞体外和小鼠体内的钠碘转运蛋白（NIS）和甲状腺素（Tg），而不改变垂体-甲状腺轴。与Mergler博士合作，我们发现3-T1 AM在各种细胞类型中快速激活质膜瞬时受体电位冷通道M8（TRPM 8），与细胞内钙信号的改变和热TRPV 1通道活性的抑制相关，从而导致细胞功能的改变。我们与Höfig博士一起鉴定了鸟氨酸脱羧酶（ODC）作为从激素原T4和THM 3，5-T2产生3-T1 AM的催化剂。这两种THM，3，5-T2和3-T1 AM以细胞类型特异性方式对细胞能量代谢发挥不同的作用，如Seahorse细胞外通量分析仪所测量的。第二个资助期的目的是（1）表征推测为ODC介导的3-T1 AM生物合成，（2）分析3-T1 AM、其前体和代谢物对a）甲状腺功能和B）胰岛功能（尤其是胰高血糖素分泌）的影响。这些目标将使用从胚胎干细胞和原代甲状腺培养物体外生长的功能性小鼠甲状腺滤泡以及胰高血糖素分泌α细胞系和分离的小鼠胰岛来解决。基因和蛋白质组表达分析与机制和功能研究相结合，将增强我们对THM，特别是3-T1 AM的生物合成和细胞特异性作用的认识，从而有助于更好地理解非经典THM的（病理）生理代谢特征。