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

Abstract:

: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.

authors

Nofsinger RR,Li P,Hong SH,Jonker JW,Barish GD,Ying H,Cheng SY,Leblanc M,Xu W,Pei L,Kang YJ,Nelson M,Downes M,Yu RT,Olefsky JM,Lee CH,Evans RM

doi

10.1073/pnas.0811012105

subject

Has Abstract

pub_date

2008-12-16 00:00:00

pages

20021-6

issue

50

eissn

0027-8424

issn

1091-6490

pii

0811012105

journal_volume

105

pub_type

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