The
ligand-dependent competing actions of
nuclear receptor (NR)-associated transcriptional
corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of
retinoid and
thyroid hormone receptors (SMRT)(mRID1) in which targeted disruption of the first receptor interaction domain (RID) of the nuclear
corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and
insulin resistance. Although apparently normal when chow fed, SMRT(mRID1) mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked
lipid accumulation in white and brown adipose tissue and the liver. The increased
weight gain of SMRT(mRID1) mice on a high-fat diet occurs predominantly in fat with adipocyte
hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRT(mRID1) mice are both
insulin-insensitive and refractory to the
glucose-lowering effects of TZD and
AICAR. Increased serum
cholesterol and
triglyceride levels were observed, accompanied by increased
leptin and decreased
adiponectin levels. Aberrant storage of
lipids in the liver occurred as
triglycerides and
cholesterol significantly compromised hepatic function.
Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR
corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of
metabolic diseases.