SMRT repression of nuclear receptors controls the adipogenic set point and metabolic homeostasis

The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of S...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-12, Vol.105 (50), p.20021-20026
Main Authors: Nofsinger, Russell R, Li, Pingping, Hong, Suk-Hyun, Jonker, Johan W, Barish, Grant D, Ying, Hao, Cheng, Sheue-yann, LeBlanc, Mathias, Xu, Wei, Pei, Liming, Kang, Yeon-Joo, Nelson, Michael, Downes, Michael, Yu, Ruth T, Olefsky, Jerrold M, Lee, Chih-Hao, Evans, Ronald M
Format: Article
Language:English
Subjects:
Adipocytes
Adipogenesis - genetics
Animals
Biological Sciences
Cell lines
Chromatin Immunoprecipitation
Co repressor proteins
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Down-Regulation
Gene Expression Regulation
Gene Knock-In Techniques
Genes
Genes, Lethal
Genetic mutation
Glucose
Glucose - metabolism
Homeostasis - genetics
Hormones
Insulin
Ligands
Lipogenesis
Metabolism
Mice
Mice, Mutant Strains
Mutation
Nuclear Receptor Co-Repressor 2
PPAR gamma - metabolism
Protein Structure, Tertiary
Repression
Repressor Proteins - genetics
Repressor Proteins - metabolism
Rodents
Thyroid Hormone Receptors alpha - genetics
Thyroid Hormone Receptors beta - genetics
Thyroid Hormones - metabolism
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Summary:The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of SMRT (SMRTmRID) that solely disrupts its interaction with nuclear hormone receptors (NHRs). SMRTmRID mice are viable and exhibit no gross developmental abnormalities, demonstrating that the reported lethality of SMRT knockouts is determined by non-NHR transcription factors. However, SMRTmRID mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRTmRID-derived MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. Collectively, our results demonstrate that SMRT-RID-dependent repression is a key determinant of the adipogenic set point as well as an integrator of glucose metabolism and whole-body metabolic homeostasis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0811012105