Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite great progress in elucidating the transcriptional network of PPARγ, epigenetic regulation of this pathway by histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly bound to PPARγ through the co-repressor nuclear receptor (CoRNR) box 2 and repressed the transcriptional activity and adipogenic potential of PPARγ. Upon CACUL1 depletion, less SIRT1 and more LSD1 were recruited to the PPARγ-responsive gene promoter, leading to increased histone H3K9 acetylation, decreased H3K9 methylation, and PPARγ activation during adipogenesis in 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA sequencing supported the repressive role of CACUL1 in PPARγ activation and fat accumulation. Finally, we confirmed CACUL1 function in human adipose-derived stem cells. Overall, our data suggest that CACUL1 tightly regulates PPARγ signaling through the mutual opposition between SIRT1 and LSD1, providing insight into its potential use for anti-obesity treatment.
Highlights
When Peroxisome proliferator-activated receptor γ (PPARγ) is bound by a ligand, such as endogenous arachidonic acid metabolites or the synthetic agonist thiazolidinedione (TZD), it forms a heterodimer with the retinoid X receptor (RXR), which allows binding to the PPAR-response element (PPRE) in the promoter of adipogenic genes, such as adipocyte protein 2 and lipoprotein lipase (LPL)[9]
We report that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, physically interacts with PPARγ and represses its transcriptional activity, suppressing adipocyte differentiation
CACUL1 interacts with PPARγ Given our previous study and mapping data, we addressed whether CACUL1 participates in SIRT1mediated nuclear receptor (NR) regulation
Summary
The worldwide increase in obesity is significantly correlated with various metabolic diseases, such as type II diabetes, hypertension, cardiovascular disease, and cancer[1]. Obesity is closely associated with increased adipocyte number and size, and excessive lipid accumulation in adipose tissues due to an imbalance between energy intake and expenditure[2,3]. Any strategies for inhibiting adipocyte differentiation (known as adipogenesis) that contribute to a reduction in adipose tissue attract considerable interest as a potential treatment for obesity. Adipogenesis is the multistep process of growth arrest, clonal expansion, and terminal differentiation of preadipocytes into mature adipocytes, accompanied by PPARγ is a ligand-activated transcription factor that belongs to the nuclear receptor (NR) superfamily[8]. When PPARγ is bound by a ligand, such as endogenous arachidonic acid metabolites or the synthetic agonist thiazolidinedione (TZD), it forms a heterodimer with the retinoid X receptor (RXR), which allows binding to the PPAR-response element (PPRE) in the promoter of adipogenic genes, such as adipocyte protein 2 (aP2, called fatty acid binding protein 4 or Fabp4) and lipoprotein lipase (LPL)[9]. The transcriptional activity of PPARγ is diversely regulated through associations with various coactivators and corepressors, many of which are histone-modifying enzymes that target histone acetylation or methylation[10]
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