Endocrine Abstracts

The endogenous thyroid hormone metabolite 3,5-diiodothyronine (3,5-T2) has attracted attention as a metabolically active substance modulating metabolism via classical thyroid hormone (TH) receptor-dependent and rapid plasma membrane, cytosolic and mitochondrial signaling pathways. Accordingly, 3,5-T2 has been proposed as a potential hypolipidaemic agent without inducing thyromimetic effects and is frequently used as illicit weight-reducing agent. The objective of the present study was to investigate 3,5-T2 effects on energy and lipid metabolism in a mouse model of diet-induced obesity. Adult male mice received either 3,5-T2 (2.5 μg/g bw) or saline i.p. over 28 days. Contrary to our expectations the heart weight strongly increased by 26 percent with 3,5-T2 treatment. Because only limited data are currently available about 3,5-T2 effects on heart, we started to investigate the potential role of 3,5-T2 in cardiac remodeling and hypertrophy. The results in 3,5-T2 exposed heart tissue indicate that 3,5-T2 modulates expression of TH responsive cardiac genes. The gene expression of Ca⁺⁺-ATPase (Serca2a2) was significantly increased while protein and gene expression of the Ca⁺⁺-ATPase inhibitor phospholamban was decreased. Interestingly, 3,5-T2 application enhanced transcript concentration of myosin heavy chain β (Myh7) and of the brain natriuretic peptide (Nppb) and reduced the mRNA concentration of TH receptor alpha (Thra) indicating a potential role of 3,5-T2 in activation of a cardiac fetal gene program and involvement of non-classical TH signaling pathways. To understand the molecular basis and to identify possible mechanisms we used the cardiomyocyte cell line H9c2. LC-MS/MS data reveal a preferential uptake of 3,5-T2 compared to classical thyroid hormones. Moreover, first findings in differentiated cardiomyoblasts show that 3,5-T2 (100nM) increased the gene expression of Ca⁺⁺-ATPase and β-MHC comparable to the in vivo data. In conclusion, our results suggest that 3,5-T2 treatment in mice alters expression of cardiac genes and might exert profound possibly adverse cardiac and cardiovascular effects.

Disclosure: DFG grant KFO 218 TP3 KO 922-18/1.