Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis

ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite a large progress on the transcriptional network of PPARγ, the epigenetic regulation associated with histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly binds to PPARγ through the CoRNR box 2 and represses the transcription activity and adipogenic potential of PPARγ. Upon CACUL1 depletion, less SIRT1 and more LSD1 was recruited to the PPARγ-responsive gene promoter, leading to the increased histone H3K9 acetylation and decreased H3K9 methylation for PPARγ activation during adipogenesis of 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA-seq supported the repressive role of CACUL1 in PPARγ activation and fat accumulation. Finally, we confirmed the 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 additional insight into its use for anti-obesity treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE105055 | GEO | 2017/10/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis.

Project description: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.

| S-EPMC5870580 | biostudies-literature

A PPARγ-lncRNA axis modulatesthermoneutral remodeling of white adipose tissue

Project description:Interplay between parenchymal energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of cellular origin or specialized niche, adipocytes require the activity of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ, however, the molecular mechanisms by which PPARγ licenses white adipose tissue (WAT) to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ-long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity (DIO). Pharmacologic inhibition or genetic deletion of the lncRNA Lexis, enhances UCP-1 dependent and independent thermogenesis. Adipose tissue specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT signaling that preserves white adipose tissue plasticity.

2023-09-27 | GSE215870 | GEO

High Fat Diet Triggers SIRT1 Cleavage in Adipose Tissue Providing a Link between Dietary Stress and Metabolic Dysfunction.

Project description:Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from the development of inflammation and obesity under normal feeding conditions, and the progression to metabolic dysfunction under dietary stress. Genetic ablation of SIRT1 from adipose tissue leads to gene expression changes that highly overlap with changes induced by high fat diet in wild type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high fat diet induces the cleavage of SIRT1 in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction. Four replicates from four different biological conditions: 1) SIRT1 wild-type fed low fat diet, 2) SIRT1 wild-type fed high fat diet, 3) SIRT1 knock-out fed low fat diet, 4) SIRT1 knock-out fed high fat diet

2012-12-21 | E-GEOD-30247 | biostudies-arrayexpress

A PPARγ-lncRNA axis modulates thermoneutral remodeling of white adipose tissue

2023-09-27 | GSE216272 | GEO

PPARgamma ubiquitination sites in HEK293T cells

Project description:Peroxisome proliferator–activated receptor γ (PPARγ) is the central regulator of adipogenesis, and its dysregulation is linked to obesity and metabolic diseases. Identification of the factors that regulate PPARγ expression and activity is therefore crucial for combating obesity. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with a known role in xenobiotic detoxification. Recent studies have suggested that AhR also plays essential roles in energy metabolism. However, the detailed mechanisms remain unclear. We previously reported that experiments with adipocyte-specific Cullin 4b (Cul4b)-knockout mice showed that CUL4B suppresses adipogenesis by targeting PPARγ. Here, using immunoprecipitation, ubiquitination, real-time PCR and Gst-pulldown assays, we report that AhR functions as the substrate receptor in CUL4B–RING E3 ubiquitin ligase (CRL4B) complex and is required for recruiting PPARγ. AhR overexpression reduced PPARγ stability and suppressed adipocyte differentiation, and AhR knockdown stimulated adipocyte differentiation in 3T3-L1 cells. Furthermore, we found that two lysine sites on residues 268 and 293 in PPARγ are targeted for CRL4B-mediated ubiquitination, indicating cross-talk between acetylation and ubiquitination. Our findings establish a critical role of AhR in regulating PPARγ stability and suggest that the AhR–PPARγ interaction may represent a potential therapeutic target for managing metabolic diseases arising from PPARγ dysfunction.

2019-11-01 | PXD015830 | Pride

A PPARγ-lncRNA axis modulates thermoneutral remodeling of white adipose tissue [snRNA-seq]

2023-09-27 | GSE216608 | GEO

Amorfrutins are selective PPARγ agonists with potent antidiabetic properties

Project description:Faced by an alarming incidence of metabolic diseases including obesity and type 2 diabetes worldwide, there is an urgent need for effective strategies for preventing and treating these common diseases. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a crucial role in metabolism. We isolated the amorfrutins from edible parts of the plants Glychyrrhiza foetida and Amorpha fruticosa, and identified these natural products as a new chemical class to treat insulin resistance and diabetes by selectively activating PPARγ. In contrast to existing synthetic PPARγ drugs, the amorfrutins display unique properties by separating insulin sensitization from unwanted side effects. In obese mouse models, amorfrutin treatment significantly improved important metabolic and inflammatory parameters. In summary, PPARγ activation by selective amorfrutins derived from edible biomaterial is a promising approach to combat metabolic diseases and other diseases in which PPARγ is involved in.

2012-05-02 | GSE28384 | GEO

High Fat Diet Triggers SIRT1 Cleavage in Adipose Tissue Providing a Link between Dietary Stress and Metabolic Dysfunction.

2012-12-21 | GSE30247 | GEO

PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

Project description:The peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with PPARγ function cause lipodystrophy. Structural studies indicate that PPARγ domains engage in several intra- and inter-moleuclar interactions; however, how these interactions modulate the ability of PPARγ to activate target genes in a cellular context is currently poorly understood. Here we analysed the transcriptional potential of R212Q and E379K two previously uncharacterised lipodystrophy-associated PPARγ mutants that are located in distinct PPARγ domains but are both predicted to affect intermolecular interactions. Using a combination of biochemical and genome-wide approaches we show that these mutations impair binding to an overlapping subset of enhancers that are less accessible and specifically require PPARγ for chromatin remodeling. Based on these findings we propose a model in which recruitment of PPARγ to chromatin is determined by several intermolecular interfaces. Furthermore, our data exemplify that relatively subtle molecular defects in transcription factors are sufficient to significantly affect enhancer binding and thereby transcriptional output.

2022-09-08 | PXD036589 | Pride

Mus musculus

Project description:CACUL1 reciprocally regulates SIRT1 and LSD1 for PPARγ repression and anti-adipogenesis

| PRJNA406857 | ENA