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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Nofsinger, RR; Li, P; Hong, S-H; Jonker, JW; Barish, GD; Ying, H; Cheng, S-Y; Leblanc, M; Xu, W; Pei, L; Kang, Y-J; Nelson, M; Downes, M; Yu, RT; Olefsky, JM; Lee, C-H; Evans, RM

Published Date

  • December 9, 2008

Published In

Volume / Issue

  • 105 / 50

Start / End Page

  • 20021 - 20026

PubMed ID

  • 19066220

Pubmed Central ID

  • 19066220

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0811012105

Language

  • eng