Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

G. Sebastian Hönes, Helena Rakov, John Logan, Xiao Hui Liao, Eugenie Werbenko, Andrea S. Pollard, Stine M. Præstholm, Majken S. Siersbæk, Eddy Rijntjes, Janina Gassen, Sören Latteyer, Kathrin Engels, Karl Heinz Strucksberg, Petra Kleinbongard, Denise Zwanziger, Jan Rozman, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe De Angelis, Ludger Klein-Hitpass & 8 andre Josef Köhrle, David L. Armstrong, Lars Grøntved, J. H.Duncan Bassett, Graham R. Williams, Samuel Refetoff, Dagmar Führer, Lars C. Moeller*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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 tissueand 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.

OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind114
Udgave nummer52
Sider (fra-til)E11323-E11332
ISSN0027-8424
DOI
StatusUdgivet - 2017

Fingeraftryk

Thyroid Hormone Resistance Syndrome
Thyroid Hormone Receptors
Mutation
Nucleic Acid Regulatory Sequences
DNA
Protein Isoforms
DNA receptor

Citer dette

Hönes, G. S., Rakov, H., Logan, J., Liao, X. H., Werbenko, E., Pollard, A. S., ... Moeller, L. C. (2017). Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. Proceedings of the National Academy of Sciences of the United States of America, 114(52), E11323-E11332. https://doi.org/10.1073/pnas.1706801115
Hönes, G. Sebastian ; Rakov, Helena ; Logan, John ; Liao, Xiao Hui ; Werbenko, Eugenie ; Pollard, Andrea S. ; Præstholm, Stine M. ; Siersbæk, Majken S. ; Rijntjes, Eddy ; Gassen, Janina ; Latteyer, Sören ; Engels, Kathrin ; Strucksberg, Karl Heinz ; Kleinbongard, Petra ; Zwanziger, Denise ; Rozman, Jan ; Gailus-Durner, Valerie ; Fuchs, Helmut ; De Angelis, Martin Hrabe ; Klein-Hitpass, Ludger ; Köhrle, Josef ; Armstrong, David L. ; Grøntved, Lars ; Bassett, J. H.Duncan ; Williams, Graham R. ; Refetoff, Samuel ; Führer, Dagmar ; Moeller, Lars C. / Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. I: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Bind 114, Nr. 52. s. E11323-E11332.
@article{da7cd87d8419481bab226d4ac5f275f6,
title = "Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo",
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 tissueand 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",
author = "H{\"o}nes, {G. Sebastian} and Helena Rakov and John Logan and Liao, {Xiao Hui} and Eugenie Werbenko and Pollard, {Andrea S.} and Pr{\ae}stholm, {Stine M.} and Siersb{\ae}k, {Majken S.} and Eddy Rijntjes and Janina Gassen and S{\"o}ren Latteyer and Kathrin Engels and Strucksberg, {Karl Heinz} and Petra Kleinbongard and Denise Zwanziger and Jan Rozman and Valerie Gailus-Durner and Helmut Fuchs and {De Angelis}, {Martin Hrabe} and Ludger Klein-Hitpass and Josef K{\"o}hrle and Armstrong, {David L.} and Lars Gr{\o}ntved and Bassett, {J. H.Duncan} and Williams, {Graham R.} and Samuel Refetoff and Dagmar F{\"u}hrer and Moeller, {Lars C.}",
year = "2017",
doi = "10.1073/pnas.1706801115",
language = "English",
volume = "114",
pages = "E11323--E11332",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "52",

}

Hönes, GS, Rakov, H, Logan, J, Liao, XH, Werbenko, E, Pollard, AS, Præstholm, SM, Siersbæk, MS, Rijntjes, E, Gassen, J, Latteyer, S, Engels, K, Strucksberg, KH, Kleinbongard, P, Zwanziger, D, Rozman, J, Gailus-Durner, V, Fuchs, H, De Angelis, MH, Klein-Hitpass, L, Köhrle, J, Armstrong, DL, Grøntved, L, Bassett, JHD, Williams, GR, Refetoff, S, Führer, D & Moeller, LC 2017, 'Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo', Proceedings of the National Academy of Sciences of the United States of America, bind 114, nr. 52, s. E11323-E11332. https://doi.org/10.1073/pnas.1706801115

Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. / Hönes, G. Sebastian; Rakov, Helena; Logan, John; Liao, Xiao Hui; Werbenko, Eugenie; Pollard, Andrea S.; Præstholm, Stine M.; Siersbæk, Majken S.; Rijntjes, Eddy; Gassen, Janina; Latteyer, Sören; Engels, Kathrin; Strucksberg, Karl Heinz; Kleinbongard, Petra; Zwanziger, Denise; Rozman, Jan; Gailus-Durner, Valerie; Fuchs, Helmut; De Angelis, Martin Hrabe; Klein-Hitpass, Ludger; Köhrle, Josef; Armstrong, David L.; Grøntved, Lars; Bassett, J. H.Duncan; Williams, Graham R.; Refetoff, Samuel; Führer, Dagmar; Moeller, Lars C.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 114, Nr. 52, 2017, s. E11323-E11332.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

AU - Hönes, G. Sebastian

AU - Rakov, Helena

AU - Logan, John

AU - Liao, Xiao Hui

AU - Werbenko, Eugenie

AU - Pollard, Andrea S.

AU - Præstholm, Stine M.

AU - Siersbæk, Majken S.

AU - Rijntjes, Eddy

AU - Gassen, Janina

AU - Latteyer, Sören

AU - Engels, Kathrin

AU - Strucksberg, Karl Heinz

AU - Kleinbongard, Petra

AU - Zwanziger, Denise

AU - Rozman, Jan

AU - Gailus-Durner, Valerie

AU - Fuchs, Helmut

AU - De Angelis, Martin Hrabe

AU - Klein-Hitpass, Ludger

AU - Köhrle, Josef

AU - Armstrong, David L.

AU - Grøntved, Lars

AU - Bassett, J. H.Duncan

AU - Williams, Graham R.

AU - Refetoff, Samuel

AU - Führer, Dagmar

AU - Moeller, Lars C.

PY - 2017

Y1 - 2017

N2 - 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 tissueand 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.

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 tissueand 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.

KW - Cardiometabolic effects

KW - Noncanonical signaling

KW - Skeleton

KW - Thyroid hormone action

KW - Thyroid hormone receptor

U2 - 10.1073/pnas.1706801115

DO - 10.1073/pnas.1706801115

M3 - Journal article

VL - 114

SP - E11323-E11332

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 52

ER -