Dataset Information

CircRNA expression profiles in human visceral preadipocytes and adipocytes.

ABSTRACT: Circular RNAs (circRNAs) regulate several physiological and pathological processes, but their role in visceral lipid deposition has not been explored. In the present study, human preadipocytes from visceral fat tissue (HPA?v) were induced to form adipocytes, and the circRNA expression profiles in HPA?v and adipocytes were detected using circRNA microarrays. The microarray data revealed that 2,215 and 1,865 circRNAs were significantly up? and downregulated, respectively, in adipocytes compared with HPA?v. Moreover, the parental genes of differentially expressed circRNAs were associated with fatty acid metabolism based on Kyoto Encyclopedia of Genes and Genomes analysis. Three circRNAs (hsa_circ_0136134, hsa_circ_0017650, and hsa?circRNA9227?1) were selected for quantitative PCR (qPCR) validation, and the qPCR results were consistent with the microarray results. Furthermore, MiRanda software was used to predict the microRNAs (miRNAs) potentially targeting the top 10 up? and downregulated circRNAs, and 14 miRNAs with more than two miRNA response elements targeting these circRNAs. This is the first study of the expression profiles of circRNAs in HPA?v and adipocytes and may suggest potential therapeutic targets for the visceral obesity.

SUBMITTER: Sun W

PROVIDER: S-EPMC6947878 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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CircRNA expression profiles in human visceral preadipocytes and adipocytes.

Sun Wenxing W Sun Xuecheng X Chu Weiwei W Yu Shigang S Dong Fulu F Xu Guangfei G

Molecular medicine reports 20191216 2

Circular RNAs (circRNAs) regulate several physiological and pathological processes, but their role in visceral lipid deposition has not been explored. In the present study, human preadipocytes from visceral fat tissue (HPA‑v) were induced to form adipocytes, and the circRNA expression profiles in HPA‑v and adipocytes were detected using circRNA microarrays. The microarray data revealed that 2,215 and 1,865 circRNAs were significantly up‑ and downregulated, respectively, in adipocytes compared wi ...[more]

PMID: 31974620

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Project description:Visceral adipose tissue contributes to the pathophysiology of metabolic syndrome. Metformin has been reported to suppress lipogenesis in a murine preadipocyte cell line. However, the effect of metformin on the differentiation of human visceral adipose tissue remains unknown. MicroRNAs (miRNAs or miRs) have been suggested as therapeutic targets because of their involvement in the differentiation and maturation of fatty cells. The aim of this study was to determine whether metformin suppresses the differentiation of human preadipocytes and to identify miRNAs associated with the regulation of lipid metabolism. Human visceral preadipocytes (HPrAD-vis) were preincubated in growth media and then cultured with differentiation media containing metformin for 1 or 2 weeks. Adipogenic differentiation of the cells was assessed by Oil Red O staining, and soluble adiponectin in the culture media was measured using an enzyme-linked immunosorbent assay. Cell proliferation was assessed using a WST-8 assay, and the gene and protein expression of peroxisome proliferator-activated receptor ? (PPAR?) and CCAAT?enhancer-binding protein ? (C/EBP?) was determined by RT-qPCR and western blot analysis, respectively. miRNAs were profiled using human miRNA Oligo chips after total RNA was extracted and labeled. Oil Red O staining showed that metformin suppressed the accumulation of lipid droplets in HPrAD-vis cells. The adiponectin concentration in the culture media was also decreased in metformin-treated cells. The WST-8 assay revealed no effect on proliferation or growth inhibition following metformin treatment, although metformin suppressed the expression of PPAR? and C/EBP?. miRNA profiling further revealed differences between the metformin-treated group and control HPrAD-vis cells. Thus, the findings of the present study demonstrated that metformin suppressed the differentiation of human preadipocytes in vitro and altered the miRNA profile of these cells. Thus, the miRNAs whose expression levels were altered by metformin may contribute to the observed suppression of HPrAD-vis cell differentiation.

Project description:Rationale: Genome-wide association studies have identified genetic loci associated with insulin resistance (IR) but pinpointing the causal genes of a risk locus has been challenging. Objective: To identify candidate causal genes for IR, we screened regional and biologically plausible genes (16 in total) near the top 10 IR-loci in risk-relevant cell types, namely preadipocytes and adipocytes. Methods and Results: We generated 16 human Simpson-Golabi-Behmel syndrome preadipocyte knockout lines each with a single IR-gene knocked out by lentivirus-mediated CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system. We evaluated each gene knockout by screening IR-relevant phenotypes in the 3 insulin-sensitizing mechanisms, including adipogenesis, lipid metabolism, and insulin signaling. We performed genetic analyses using data on the genotype-tissue expression portal expression quantitative trait loci database and accelerating medicines partnership type 2 diabetes mellitus Knowledge Portal to evaluate whether candidate genes prioritized by our in vitro studies were expression quantitative trait loci genes in human subcutaneous adipose tissue, and whether expression of these genes is associated with risk of IR, type 2 diabetes mellitus, and cardiovascular diseases. We further validated the functions of 3 new adipose IR genes by overexpression-based phenotypic rescue in the Simpson-Golabi-Behmel syndrome preadipocyte knockout lines. Twelve genes, PPARG, IRS-1, FST, PEPD, PDGFC, MAP3K1, GRB14, ARL15, ANKRD55, RSPO3, COBLL1, and LYPLAL1, showed diverse phenotypes in the 3 insulin-sensitizing mechanisms, and the first 7 of these genes could affect all the 3 mechanisms. Five out of 6 expression quantitative trait loci genes are among the top candidate causal genes and the abnormal expression levels of these genes (IRS-1, GRB14, FST, PEPD, and PDGFC) in human subcutaneous adipose tissue could be associated with increased risk of IR, type 2 diabetes mellitus, and cardiovascular disease. Phenotypic rescue by overexpression of the candidate causal genes (FST, PEPD, and PDGFC) in the Simpson-Golabi-Behmel syndrome preadipocyte knockout lines confirmed their function in adipose IR. Conclusions: Twelve genes showed diverse phenotypes indicating differential roles in insulin sensitization, suggesting mechanisms bridging the association of their genomic loci with IR. We prioritized PPARG, IRS-1, GRB14, MAP3K1, FST, PEPD, and PDGFC as top candidate genes. Our work points to novel roles for FST, PEPD, and PDGFC in adipose tissue, with consequences for cardiometabolic diseases.

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CircRNA expression profiles in human visceral preadipocytes and adipocytes.

Publications

CircRNA expression profiles in human visceral preadipocytes and adipocytes.

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