Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

G. Sebastian Hönes, Helena Rakov, John Logan, Xiao Hui Liao, Eugenie Werbenko, Andrea S. Pollard, Stine M. Præstholm, Majken S. Siersbæk, Eddy Rijntjes, Janina Gassen, Sören Latteyer, Kathrin Engels, Karl Heinz Strucksberg, Petra Kleinbongard, Denise Zwanziger, Jan Rozman, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe De Angelis, Ludger Klein-HitpassJosef Köhrle, David L. Armstrong, Lars Grøntved, J. H.Duncan Bassett, Graham R. Williams, Samuel Refetoff, Dagmar Führer, Lars C. Moeller*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


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 tissueand 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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
Pages (from-to)E11323-E11332
Publication statusPublished - 2017


  • Cardiometabolic effects
  • Noncanonical signaling
  • Skeleton
  • Thyroid hormone action
  • Thyroid hormone receptor


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