Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 50, Pages 20021-20026Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0811012105
Keywords
adipogenesis; corepressor; PPAR; TR; glucose regulation
Categories
Funding
- Molecular Cardiology Training Grant [T32 HL07770-14]
- Human Frontier Science Program
- American Heart Association and American Diabetes Association
- National Institutes of Health [R01DK075046]
- Howard Hughes Medical Institute and National Institutes of Health [5R37DK057978, 5R01HD027183]
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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.
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