Imperial College London
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ProfessorGrahamWilliams

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Clinical Professor of Endocrinology
 
 
 
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Contact

 

+44 (0)20 3313 1383graham.williams

 
 
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Location

 

10N5Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hönes:2017:10.1073/pnas.1706801115,
author = {Hönes, GS and Rakov, H and Logan, J and Liao, X-H and Werbenko, E and Pollard, AS and Præstholm, SM and Siersbæk, MS and Rijntjes, E and Gassen, J and Latteyer, S and Engels, K and Strucksberg, K-H and Kleinbongard, P and Zwanziger, D and Rozman, J and Gailus-Durner, V and Fuchs, H and Hrabe, de Angelis M and Klein-Hitpass, L and Köhrle, J and Armstrong, DL and Grøntved, L and Bassett, JHD and Williams, GR and Refetoff, S and Führer, D and Moeller, LC},
doi = {10.1073/pnas.1706801115},
journal = {Proc Natl Acad Sci U S A},
pages = {E11323--E11332},
title = {Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo.},
url = {http://dx.doi.org/10.1073/pnas.1706801115},
volume = {114},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Hönes,GS
AU  - Rakov,H
AU  - Logan,J
AU  - Liao,X-H
AU  - Werbenko,E
AU  - Pollard,AS
AU  - Præstholm,SM
AU  - Siersbæk,MS
AU  - Rijntjes,E
AU  - Gassen,J
AU  - Latteyer,S
AU  - Engels,K
AU  - Strucksberg,K-H
AU  - Kleinbongard,P
AU  - Zwanziger,D
AU  - Rozman,J
AU  - Gailus-Durner,V
AU  - Fuchs,H
AU  - Hrabe,de Angelis M
AU  - Klein-Hitpass,L
AU  - Köhrle,J
AU  - Armstrong,DL
AU  - Grøntved,L
AU  - Bassett,JHD
AU  - Williams,GR
AU  - Refetoff,S
AU  - Führer,D
AU  - Moeller,LC
DO  - 10.1073/pnas.1706801115
EP  - 11332
PY  - 2017///
SP  - 11323
TI  - Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo.
T2  - Proc Natl Acad Sci U S A
UR  - http://dx.doi.org/10.1073/pnas.1706801115
UR  - https://www.ncbi.nlm.nih.gov/pubmed/29229863
UR  - http://hdl.handle.net/10044/1/54928
VL  - 114
ER  -
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