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Hönes, G.S.* ; Rakov, H.* ; Logan, J.* ; Liao, X.-H.* ; Werbenko, E.* ; Pollard, A.S.* ; Præstholm, S.M.* ; Siersbæk, M.S.* ; Rijntjes, E.* ; Gassen, J.* ; Latteyer, S.* ; Engels, K.* ; Strucksberg, K.-H.* ; Kleinbongard, P.* ; Zwanziger, D.* ; Rozman, J. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Klein-Hitpass, L.* ; Köhrle, J.* ; Armstrong, D.L.* ; Grøntved, L.* ; Basset, J.H.D.* ; Williams, G.R.* ; Refetoff, S.* ; Führer, D.* ; Moeller, L.C.*

Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo.

Proc. Natl. Acad. Sci. U.S.A. 114, E11323-E11332 (2017)
Verlagsversion DOI PMC
Free by publisher
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter thyroid hormone receptor; noncanonical signaling; thyroid hormone action; skeleton; cardiometabolic effects; Receptor Dna-binding; Plasma-membrane; Gene-expression; Serum-lipids; L-thyroxine; Tr-beta; Mice; Resistance; Alpha; Thyrotropin
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 114, Heft: 52, Seiten: E11323-E11332 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Verlagsort Washington
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)