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Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance.

ABSTRACT: 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.

SUBMITTER: Fang S

PROVIDER: S-EPMC3044388 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance.

Fang Sungsoon S Suh Jae Myoung JM Atkins Annette R AR Hong Suk-Hyun SH Leblanc Mathias M Nofsinger Russell R RR Yu Ruth T RT Downes Michael M Evans Ronald M RM

Proceedings of the National Academy of Sciences of the United States of America 20110207 8

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 sub ...[more]

PMID: 21300871

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Project description:ABSTRACT OBJECTIVE: Genome Wide Association Studies (GWAS) in humans, dogs, and livestock have uncovered genes which may play a role in metabolism. However, functional analysis is required to link the metabolic phenotype with the associated gene. Here we identified the Ligand Dependent Corepressor-Like (LCoRL) as a potential metabolic regulator. METHOD: We used CRISPR/Cas9 approaches in mice to generate a Lcorl null allele (Lcorl-/-). We characterized Lcorl-/- mice by assessing body weight, body composition, food intake, and glucose homeostasis as well as assessing transcriptional changes in Lcorl-/- livers by RNA-sequencing. Finally, we challenged mice with a 60% high fat diet (HFD) and a treadmill exercise stress test. RESULTS: Mice homozygous for loss of Lcorl are viable and fertile. However, Lcorl-/- pups show stunted postnatal growth for the first few weeks of life. This is followed by a catchup growth, such that, Lcorl-/- mice are indistinguishable from wildtype littermates by 7-9 weeks of age. Three-week-old mice show reduced circulating insulin like growth factor-1 (IGF-1) levels without a change in pituitary Growth hormone (Gh) mRNA levels. Interestingly, Lcorl-/- mice remain lean compared to wildtype littermates as they age. This is associated with a decrease in daily food intake. Additionally, Lcorl-/- mice show no change in energy expenditure; however, Lcorl-/- mice show a greater amplitude of their respiratory exchange ratio (RER) compared to controls, suggesting differential usage of fat and carbohydrates across the light/dark cycle. This altered RER may result from the reduction in day-time food intake or disrupted mobilization of fat and carbohydrate stores. Consistent with enhanced metabolic health, Lcorl-/- mice also show improved glucose tolerance and insulin sensitivity. Finally, Lcorl-/- mice are protected against a 60% high fat diet challenge and show reduced exercise capacity in a stress test. CONCLUSION: This phenotypic characterization of the Lcorl-/- mouse reveals that LCoRL is a causal gene resulting in the changes in metabolism seen in GWAS in humans and livestock and provides novel mechanistic insights of a gene important in human disease and economically valuable traits in livestock.

Dataset Information

Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance.

Publications

Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance.

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