Anti-adipogenesis effect of indole-3-acrylic acid on human preadipocytes and HFD- induced zebrafish
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PROVIDER: PRJNA1034981 | ENA |
REPOSITORIES: ENA
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Project description:Obesity, defined as excessive or abnormal body fat accumulation, which could significantly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) diseases and seriously affect people's quality of life. More than 2 billion people are overweight, and the incidence of obesity is increasing rapidly worldwide, it has become a widely concerned public health issue in the world. Diverse evidence show that active metabolites are involved in the pathophysiological processes of obesity. However, whether the downstream catabolite of tryptophan, 3-indole acrylic acid (IA), is involved in obesity remains unclear. Here, we found that the content of IA in peripheral blood serum of overweight people was significantly lower than that of normal people. In addition, supplementation with IA in zebrafish larvae induced by a high fat diet (HFD) dramatically reduced HFD induced lipid accumulation. IA had no effect on proliferation and apoptosis of preadipocytes, but significantly inhibited adipogenesis of preadipocytes by down-regulate CEBPα and PPARγ. RNA-Seq and functional analysis revealed that IA regulated the adipogenesis of preadipocytes through stimulate the phosphorylation of STAT1. Taken together, IA has been identified as a potent metabolite for the prevention or treatment of obesity.
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Project description:The Wnt/b-catenin signaling inhibits adipogenesis. Genome-wide profiling studies have revealed the enrichment of histone H3K27 methyltransferase PRC2 on Wnt genes. However, the functional significance of such a direct link between the two types of developmental regulators in mammalian cells, and the role of PRC2 in adipogenesis, remain unclear. Here we show PRC2 and its H3K27 methyltransferase activity are required for adipogenesis. PRC2 directly represses Wnt1, 6, 10a and 10b genes in preadipocytes and during adipogenesis. Deletion of the enzymatic Ezh2 subunit of PRC2 eliminates H3K27me3 on Wnt promoters and de-represses Wnt expression, which leads to activation of Wnt/b-catenin signaling and inhibition of adipogenesis. Ectopic expression of the wild type Ezh2, but not the enzymatically inactive F667I mutant, prevents the loss of H3K27me3 and the defects in adipogenesis in Ezh2-/- preadipocytes. The adipogenesis defects in Ezh2-/- cells can be rescued by expression of adipogenic transcription factors PPARa, C/EBPb, or inhibitors of Wnt/b-catenin signaling. Interestingly, Ezh2-/- cells show marked increase of H3K27 acetylation globally as well as on Wnt promoters. These results indicate that H3K27 methyltransferase PRC2 directly represses Wnt genes to facilitate adipogenesis, and suggest that acetylation and trimethylation on H3K27 play opposing roles in regulating Wnt expression. To identify additional PRC2-regulated genes in preadipocytes, we performed microarray analysis in Ezh2flox/flox preadipocytes infected with retroviruses expressing Cre or vector alone.
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Project description:Local hypoxia is recently reported to be occur in white adipose tissue (WAT) microenvironment at obesity. Adipocyte have own life cycle that reflect in different stages of adipogenesis in WAT niche. Long noncoding RNAs (lncRNAs) play an important role in cellular response to hypoxia. However, the different hypoxic responses of preadipocytes during adipogenesis and the potential role of lncRNAs in this process remain to be elucidated. Here we evaluated the different hypoxic responses of primary hamster preadipocytes during adipogenesis and analyzed the expression of mRNAs and lncRNAs from same Ribo-Zero RNA-seq libraries. Hypoxia induced HIF-1α protein during adipogenesis and caused the divergent changes of cell phenotypes. A total of 10,318 mRNAs were identified to be expressed in twenty libraries (five timepoints), and 149, 326, 365, 1099, 2504 differentially expressed mRNAs (DE mRNAs) were detected in D0, D1, D3, D7 and D11, respectively (hypoxia vs normoxia). Functional enrichment analysis revealed the shared and specific hypoxia response pathways in different stages of adipogenesis. Hypoxia differentially modulates the expression profile of adipose-associated genes, including adipokines, lipogenesis, lipolysis, hyperplasia, hypertrophy, inflammatory and extracellular matrix (ECM). We also identified 4,296 lncRNAs that were substantially expressed and detected 1,431 DE lncRNAs in five timepoints. Afterward, 2, 3, 5, 13 and 50 DE mRNAs in D0, D1, D3, D7 and D11, respectively, were highly correlated and loci-nearby with DE lncRNAs, and were mainly involved in cell cycle, vesicle-mediated transport and mitochondrion organization. We also identified twenty-eight one-to-one lncRNA-mRNA pairs that might be closely related to adipocyte function, such as ENSCGRT00015041780-Hilpda, TU2105-Cdsn, TU17588-Ltbp3. These lncRNAs may represent the crucial regulation axis in cellular response to hypoxia during adipogenesis. Altogether, this study dissected the effects of hypoxia in the cell during adipogenesis, and uncovered novel regulator potentially associated with obesity and may provide a new view for interpretation and treatment of obesity.
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Project description:PPARγ promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is enriched on the entire PPARγ locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPARγ. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBP-beta to PPARγ promoter, which promotes PPARγ expression. Interestingly, G9a represses PPARγ expression in an HMT activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Consistently, deletion of G9a or inhibiting G9a HMT activity promotes adipogenesis. Finally, deletion of G9a in mouse adipose tissues increases adipogenic gene expression and tissue weight. Thus, by inhibiting PPARγ expression and facilitating Wnt10a expression, G9a represses adipogenesis. Examination of gene expression changes in G9a KO brown preadipocytes
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Project description:To investigate miRNAs that implicate the process of adipogenesis by interacting with canonical Wnt/β-catenin signaling pathway, we constructed two cell models at first, and then investigated the expression profile of microRNAs by using Microarray. Based on the data of high throughput microarray, we identified 18 miRNAs which might promote adipogenesis by repressing WNT signaling, including mir-210, mir-148a, mir-194, mir-322 etc. On the other hand, we also identified 29 miRNAs which might repress adipogenesis by activation of WNT signaling, including mir-344, mir-27, and mir-181. The target genes involved in WNT signaling pathway of these identified miRNAs were also predicted through online tools. Two cell models of 3T3-L1, i.e. activation and suppression of WNT signaling including four samples, i.e. preadipocytes, mature adipocytes (MDI induction), Lithium treated preadipocytes, MDI induction of Lithium treated preadipocytes. Each sample was replicated in triplicate.
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Project description:Full title: Expression data from human primary subcutaneous preadipocytes treated with glucocorticoids prior to the initiation of differentiation. Preadipocytes are continuously exposed to glucocorticoids in situ due to both steroid present in the circulatory system as well as adipose tissue specific 11βHSD1 activity. While the effects of glucocorticoids during differentiation are well studied, the effect of exposure of preadipocytes to glucocorticoids prior to differentiation is unknown. We therefore treated confluent human primary preadipocytes drived from subcutaneous adipose tissue with the synthetic glucocorticoid dexamethasone for 48 hours prior to the initiation of differentiation and assessed what effect this had on their subsequent potential to differentiate. We found that pretreatment with glucocorticoids had a priming effect and resulted in increased differentiation of these preadipocytes. Furthermore, this treatment was additive to the effects of glucocorticoids during the initial phase of adipogenesis. Microarray analysis performed subsequent to the pretreatment with glucocorticoids (at the time point at which preadipocytes would have been induced to differentiate) identified glucocorticoid-responsive, candidate genes whose altered expression could mediate these effects. keywords: glucocorticoids, glucocorticoid receptor, preadipocytes, adipogenesis, human primary preadipocytes, subcutaneous, adipose tissue
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