Non-classical thyroid hormone action mediated by thyroid hormone receptor alpha and beta

• Applicant: Professor Dr. Lars Möller
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221205689

Thyroid hormones (TH) are essential for normal development, growth, and metabolism. They act as ligands of the thyroid hormone receptors (TRs) alpha and beta. The TRs reside on the promoters of target genes and induce gene expression after hormone binding, which is seen as their classical mode of action. Recently, it was discovered that TRs can also act independent of DNA binding: they can activate a cellular signaling pathway, the PI3K pathway, which then also induces gene expression, but may also mediate other physiological effects of TH. This is characterized as non-classical TH action. The physiological relevance of non-classical TH action is currently unknown. The challenge is now to determine which effects of TH are mediated through which of the two mechanisms of the TRs, classical (DNA-dependent) or non-classical (DNA-independent). We therefore generated mouse models for the TRs, in which the TRs were modified so that they cannot bind to DNA anymore, the TRalphaGS and the TRbetaGS mice. All effects of TH mediated by these receptors must therefore be DNA-independent. These mice are viable and fertile and allow us to study purely non-classical, DNA-independent effects of TH in a live animal model in comparison to TR wild-type (WT) and TR knock-out (KO) mice: TH effects that are observed in TR WT mice, absent in TR KO mice, but preserved in TR GS mice must be dependent on TRs, but independent from DNA binding, constituting non-classical TH action. Preliminary phenotyping showed that the phenotype of TRalphaGS and TRbetaGS mice is not the same as that of TRalpha or TRbeta (KO) mice: Heart rate is maintained in TRalphaGS mice and not reduced as seen in TRalphaKO mice, TH treatment leads to a shift from slow to fast fibers in muscle from TRbetaGS mice but not from TRbetaKO mice, TH treatment rapidly decreases blood glucose in TRbetaGS mice, but not in TRbetaKO mice, and TRbetaGS mice have a higher body temperature than TRbetaKO mice.These preliminary data strongly suggest that non-classical TR signaling is relevant in vivo, which challenges the current paradigm that the main TH effects are determined by the genes that are induced via classical TR action on their promoters. Aim of this project, therefore, is to study the contribution of non-classical TH action to the overall effect of TH using the TRalphaGS and TRbetaGS mice with absent classical TH action as suitable models. The specific aims are: 1) To determine where and how non-classical TH action via TRbeta activates thermogenesis, 2) to determine the role of non-classical TH action via TRbeta in pancreatic beta-cell function, 3) to determine the role of non-classical TH action via TRalpha in cardiac hypertrophy. This project will advance our understanding of TH action and especially of the physiological relevance of non-classical TH action mediated by the TRs alpha and beta.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1629: THYROID TRANS ACT - Translation of Thyroid Hormone Actions beyond Classical Concepts
• International Connection: USA
• Cooperation Partner: Professor Dr. Samuel Refetoff