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

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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.