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Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11323-E11332. doi: 10.1073/pnas.1706801115. Epub 2017 Dec 11.

Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo.

Author information

1
Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
2
Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
3
Department of Medicine, The University of Chicago, Chicago, IL 60637.
4
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark.
5
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, 10117 Berlin, Germany.
6
Institute for Pathophysiology, West-German Heart and Vascular Center Essen, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
7
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
8
German Center for Diabetes Research, 85764 Neuherberg, Germany.
9
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354 Freising, Germany.
10
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, 45147 Essen, Germany.
11
Laboratory of Neurobiology, National Institute of Environmental Health and Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
12
Department of Pediatrics, The University of Chicago, Chicago, IL 60637.
13
Committee on Genetics, The University of Chicago, Chicago, IL 60637.
14
Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; lars.moeller@uni-due.de.

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.

KEYWORDS:

cardiometabolic effects; noncanonical signaling; skeleton; thyroid hormone action; thyroid hormone receptor

PMID:
29229863
PMCID:
PMC5748168
DOI:
10.1073/pnas.1706801115
[Indexed for MEDLINE]
Free PMC Article

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