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Ligand-dependent corepressor (LCoR) represses the transcription factor C/EBP? during early adipocyte differentiation.

ABSTRACT: Nuclear receptors (NRs) regulate gene transcription by recruiting coregulators, involved in chromatin remodeling and assembly of the basal transcription machinery. The NR-associated protein ligand-dependent corepressor (LCoR) has previously been shown to suppress hepatic lipogenesis by decreasing the binding of steroid receptor coactivators to thyroid hormone receptor. However, the role of LCoR in adipogenesis has not been established. Here, we show that LCoR expression is reduced in the early stage of adipogenesis in vitro LCoR overexpression inhibited 3T3-L1 adipocyte differentiation, whereas LCoR knockdown promoted it. Using an unbiased affinity purification approach, we identified CCAAT/enhancer-binding protein ? (C/EBP?), a key transcriptional regulator in early adipogenesis, and corepressor C-terminal binding proteins as potential components of an LCoR-containing complex in 3T3-L1 adipocytes. We found that LCoR directly interacts with C/EBP? through its C-terminal helix-turn-helix domain, required for LCoR's inhibitory effects on adipogenesis. LCoR overexpression also inhibited C/EBP? transcriptional activity, leading to inhibition of mitotic clonal expansion and transcriptional repression of C/EBP? and peroxisome proliferator-activated receptor ?2 (PPAR?2). However, LCoR overexpression did not affect the recruitment of C/EBP? to the promoters of C/EBP? and PPAR?2 in 3T3-L1 adipocytes. Of note, restoration of PPAR?2 or C/EBP? expression attenuated the inhibitory effect of LCoR on adipogenesis. Mechanistically, LCoR suppressed C/EBP?-mediated transcription by recruiting C-terminal binding proteins to the C/EBP? and PPAR?2 promoters and by modulating histone modifications. Taken together, our results indicate that LCoR negatively regulates early adipogenesis by repressing C/EBP? transcriptional activity and add LCoR to the growing list of transcriptional corepressors of adipogenesis.

SUBMITTER: Cao H

PROVIDER: S-EPMC5704479 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Ligand-dependent corepressor (LCoR) represses the transcription factor C/EBPβ during early adipocyte differentiation.

Cao Hongchao H Zhang Shengjie S Shan Shifang S Sun Chao C Li Yan Y Wang Hui H Yu Shuxian S Liu Yi Y Guo Feifan F Zhai Qiwei Q Wang Yu-Cheng YC Jiang Jingjing J Wang Hui H Yan Jun J Liu Wei W Ying Hao H

The Journal of biological chemistry 20170926 46

Nuclear receptors (NRs) regulate gene transcription by recruiting coregulators, involved in chromatin remodeling and assembly of the basal transcription machinery. The NR-associated protein ligand-dependent corepressor (LCoR) has previously been shown to suppress hepatic lipogenesis by decreasing the binding of steroid receptor coactivators to thyroid hormone receptor. However, the role of LCoR in adipogenesis has not been established. Here, we show that LCoR expression is reduced in the early s ...[more]

PMID: 28972158

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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

Ligand-dependent corepressor (LCoR) represses the transcription factor C/EBP? during early adipocyte differentiation.

Publications

Ligand-dependent corepressor (LCoR) represses the transcription factor C/EBPβ during early adipocyte differentiation.

Similar Datasets

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