Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.

Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) and the nuclear receptor co-repressor1 (NCoR1) are paralogs and regulate nuclear receptor (NR) function through the recruitment of a multiprotein complex that includes histone deacetylase activity. Previous genetic strategies which...

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Main Authors: Hiroaki Shimizu, Yu Lu, Kristen R Vella, Federico Damilano, Inna Astapova, Izuki Amano, Megan Ritter, Molly R Gallop, Anthony N Rosenzweig, Ronald N Cohen, Anthony N Hollenberg
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2019-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0220717
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author Hiroaki Shimizu
Yu Lu
Kristen R Vella
Federico Damilano
Inna Astapova
Izuki Amano
Megan Ritter
Molly R Gallop
Anthony N Rosenzweig
Ronald N Cohen
Anthony N Hollenberg
author_facet Hiroaki Shimizu
Yu Lu
Kristen R Vella
Federico Damilano
Inna Astapova
Izuki Amano
Megan Ritter
Molly R Gallop
Anthony N Rosenzweig
Ronald N Cohen
Anthony N Hollenberg
author_sort Hiroaki Shimizu
collection DOAJ
description Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) and the nuclear receptor co-repressor1 (NCoR1) are paralogs and regulate nuclear receptor (NR) function through the recruitment of a multiprotein complex that includes histone deacetylase activity. Previous genetic strategies which deleted SMRT in a specific tissue or which altered the interaction between SMRT and NRs have suggested that it may regulate adiposity and insulin sensitivity. However, the full role of SMRT in adult mice has been difficult to establish because its complete deletion during embryogenesis is lethal. To elucidate the specific roles of SMRT in mouse target tissues especially in the context of thyroid hormone (TH) signaling, we used a tamoxifen-inducible post-natal disruption strategy. We found that global SMRT deletion causes dramatic obesity even though mice were fed a standard chow diet and exhibited normal food intake. This weight gain was associated with a decrease in energy expenditure. Interestingly, the deletion of SMRT had no effect on TH action in any tissue but did regulate retinoic acid receptor (RAR) function in the liver. We also demonstrate that the deletion of SMRT leads to profound hepatic steatosis in the setting of obesity. This is unlike NCoR1 deletion, which results in hepatic steatosis due to the upregulation of lipogenic gene expression. Taken together, our data demonstrate that SMRT plays a unique and CoR specific role in the regulation of body weight and has no role in TH action. This raises the possibility that additional role of CoRs besides NCoR1 and SMRT may exist to regulate TH action.
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spelling doaj.art-cd1ab538c8344a8297bad9a389a8ded82022-12-21T19:10:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01148e022071710.1371/journal.pone.0220717Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.Hiroaki ShimizuYu LuKristen R VellaFederico DamilanoInna AstapovaIzuki AmanoMegan RitterMolly R GallopAnthony N RosenzweigRonald N CohenAnthony N HollenbergSilencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) and the nuclear receptor co-repressor1 (NCoR1) are paralogs and regulate nuclear receptor (NR) function through the recruitment of a multiprotein complex that includes histone deacetylase activity. Previous genetic strategies which deleted SMRT in a specific tissue or which altered the interaction between SMRT and NRs have suggested that it may regulate adiposity and insulin sensitivity. However, the full role of SMRT in adult mice has been difficult to establish because its complete deletion during embryogenesis is lethal. To elucidate the specific roles of SMRT in mouse target tissues especially in the context of thyroid hormone (TH) signaling, we used a tamoxifen-inducible post-natal disruption strategy. We found that global SMRT deletion causes dramatic obesity even though mice were fed a standard chow diet and exhibited normal food intake. This weight gain was associated with a decrease in energy expenditure. Interestingly, the deletion of SMRT had no effect on TH action in any tissue but did regulate retinoic acid receptor (RAR) function in the liver. We also demonstrate that the deletion of SMRT leads to profound hepatic steatosis in the setting of obesity. This is unlike NCoR1 deletion, which results in hepatic steatosis due to the upregulation of lipogenic gene expression. Taken together, our data demonstrate that SMRT plays a unique and CoR specific role in the regulation of body weight and has no role in TH action. This raises the possibility that additional role of CoRs besides NCoR1 and SMRT may exist to regulate TH action.https://doi.org/10.1371/journal.pone.0220717
spellingShingle Hiroaki Shimizu
Yu Lu
Kristen R Vella
Federico Damilano
Inna Astapova
Izuki Amano
Megan Ritter
Molly R Gallop
Anthony N Rosenzweig
Ronald N Cohen
Anthony N Hollenberg
Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.
PLoS ONE
title Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.
title_full Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.
title_fullStr Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.
title_full_unstemmed Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.
title_short Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action.
title_sort nuclear corepressor smrt is a strong regulator of body weight independently of its ability to regulate thyroid hormone action
url https://doi.org/10.1371/journal.pone.0220717
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