ESPEYB15 3 Thyroid Mechanisms of the year (2 abstracts)
3.4 Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo
Hones GS , Rakov H , Logan J , Liao XH , Werbenko E , Pollard AS , Praestholm SM , Siersbaek MS , Rijntjes E , Gassen J , Latteyer S , Engels K , Strucksberg KH , Kleinbongard P , Zwanziger D , Rozman J , Gailus-Durner V , Fuchs H , Hrabe de Angelis M , Klein-Hitpass L , Kohrle J , Armstrong DL , Grontved L , Bassett JHD , Williams GR , Refetoff S , Fuhrer D & Moeller LC
Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
To read the full abstract: Proc Natl Acad Sci U S A 2017;114:E11323-E11332
The mechanism of thyroid hormone (TH) action is classically attributed to thyroid hormone receptor (THR) binding to thyroid hormone responsive elements (TRE) in promotors of target genes, directly controlling gene expression in target tissues. Thus, THRs alpha (TRa) and beta (TRb) function as TH dependent transcription factors. A recent new nomenclature proposed by Flamant et al. in 2017 classified this canonical TH signaling through binding of TH to either TRa or TRb as THR-dependent signaling of TH with direct binding to DNA (type 1)1.
However, recent data described in detail a direct activation of the PI3K pathway by THR-dependent signaling without DNA binding (type 3) being essential for normal development of hippocampal synapses in the mouse2. However, besides synapse development, knowledge on the role of this noncanonical TH/THR signaling is scarce.
Here, Hones et al. used different mouse models to dissect the different roles and actions of canonical versus noncanonical TH/THR signaling. They compared in detail the phenotypes of THR knockout mice (with abolished canonical and noncanonical TH/THR signaling), with a newly generated mouse model abolishing selectively THR binding to TREs (abolished canonical signaling), but with preserved binding of TH to mutated THR (noncanonical signaling). The key findings were that the metabolic and cardiac actions of TH were not disrupted if canonical TH action (type 1, THR binding to DNA) was abolished. In summary, this paper extends our knowledge on thyroid hormone physiology by providing evidence for noncanonical type 3 TH/THR signaling (without DNA binding) by both TRa and TRb to regulate energy metabolism (body temperature, blood glucose, and lipid levels) and cardiac function (heart rate).
1. Flamant F, Cheng SY, Hollenberg AN, Moeller LC, Samarut J, Wondisford FE, Yen PM, Refetoff S. Thyroid hormone signaling pathways: time for a more precise nomenclature. Endocrinology 2017;158:2052-57.
2. Martin NP, Marron Fernandez de Velasco E, Mizuno F, Scappini EL, Gloss B, Erxleben C, Williams JG, Stapleton HM, Gentile S, Armstrong DL. A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRbeta, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology 2014;155:3713-3724.
Volume 15
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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