Non-canonical thyroid hormone signaling mediates cardiometabolic effects in vivo
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Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2017-12-26
Date Acceptance
2017-10-15
ISSN
0027-8424
Publisher
National Academy of Sciences
Start Page
E11323
End Page
E11332
Journal / Book Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
114
Issue
52
Copyright Statement
© 2017 The Authors. Published under the PNAS license.
Sponsor
Wellcome Trust
Grant Number
101123/Z/13/A
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
thyroid hormone receptor
noncanonical signaling
thyroid hormone action
skeleton
cardiometabolic effects
RECEPTOR DNA-BINDING
PLASMA-MEMBRANE
GENE-EXPRESSION
SERUM-LIPIDS
L-THYROXINE
TR-BETA
RESISTANCE
MICE
THYROTROPIN
ACTIVATION
cardiometabolic effects
noncanonical signaling
skeleton
thyroid hormone action
thyroid hormone receptor
Animals
Gene Knock-In Techniques
Hypothalamo-Hypophyseal System
Mice
Mice, Knockout
Myocardium
Pituitary-Adrenal System
Receptors, Thyroid Hormone
Signal Transduction
Thyroid Hormones
Myocardium
Pituitary-Adrenal System
Hypothalamo-Hypophyseal System
Animals
Mice, Knockout
Mice
Thyroid Hormones
Receptors, Thyroid Hormone
Signal Transduction
Gene Knock-In Techniques
Publication Status
Published
Date Publish Online
2017-12-11