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 SMRT (SMRT(mRID)) that solely disrupts its interaction with nuclear hormone receptors (NHRs). SMRT(mRID) 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, SMRT(mRID) mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRT(mRID)-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.
Nofsinger
Russell R
RR
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Li
Pingping
P
Hong
Suk-Hyun
SH
Jonker
Johan W
JW
Barish
Grant D
GD
Ying
Hao
H
Cheng
Sheue-Yann
SY
Leblanc
Mathias
M
Xu
Wei
W
Pei
Liming
L
Kang
Yeon-Joo
YJ
Nelson
Michael
M
Downes
Michael
M
Yu
Ruth T
RT
Olefsky
Jerrold M
JM
Lee
Chih-Hao
CH
Evans
Ronald M
RM
D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D005804:Genes, Lethal; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D013963:Thyroid Hormones / Q000378:metabolism
D004268:DNA-Binding Proteins; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma; D012097:Repressor Proteins; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D005947:Glucose