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.sup.mRID]) that solely disrupts its interaction with nuclear hormone receptors (NHRs). [SMRT.sup.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.sup.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.sup.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. adipogenesis | corepressor | PPAR | TR | glucose regulation