Author:
Hönes G. Sebastian,Rakov Helena,Logan John,Liao Xiao-Hui,Werbenko Eugenie,Pollard Andrea S.,Præstholm Stine M.,Siersbæk Majken S.,Rijntjes Eddy,Gassen Janina,Latteyer Sören,Engels Kathrin,Strucksberg Karl-Heinz,Kleinbongard Petra,Zwanziger Denise,Rozman Jan,Gailus-Durner Valerie,Fuchs Helmut,Hrabe de Angelis Martin,Klein-Hitpass Ludger,Köhrle Josef,Armstrong David L.,Grøntved Lars,Bassett J. H. Duncan,Williams Graham R.,Refetoff Samuel,Führer Dagmar,Moeller Lars C.
Abstract
Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding–defective TRβ leads to disruption of the hypothalamic–pituitary–thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.
Funder
Deutsche Forschungsgemeinschaft
HHS | National Institutes of Health
Wellcome
Bundesministerium für Bildung und Forschung
Publisher
Proceedings of the National Academy of Sciences