[논문]Effect of ciglitazone on adipogenic transdifferentiation of bovine skeletal muscle satellite cells

Zhang, Junfang; Li, Qiang; Yan, Yan; Sun, Bin; Wang, Ying; Tang, Lin; Wang, Enze; Yu Jia; Nogoy, Kim Margarette Corpuz; Li, Xiangzi; Choi, Seong-Ho

doi:10.5187/jast.2021.e87

Effect of ciglitazone on adipogenic transdifferentiation of bovine skeletal muscle satellite cells 원문보기

Journal of animal science and technology : JAST, v.63 no.4, 2021년, pp.934 - 953

Zhang, Junfang (Engineering Research Center of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Yanbian University) , Li, Qiang (Engineering Research Center of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Yanbian University) , Yan, Yan (Engineering Research Center of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Yanbian University) , Sun, Bin (Engineering Research Center of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Yanbian University) , Wang, Ying (Engineering Research Center of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Yanbian University) , Tang, Lin (Engineering Research Center of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Yanbian University) , Wang, Enze (Engineering Research Center of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Yanbian University) , Yu Jia , Nogoy, Kim Margarette Corpuz , Li, Xiangzi , Choi, Seong-Ho

Abstract ▼ AI-Helper

Ciglitazone is a member of the thiazolidinedione family, and specifically binds to peroxisome proliferator-activated receptor-γ (PPARγ), thereby promoting adipocyte differentiation. We hypothesized that ciglitazone as a PPARγ ligand in the absence of an adipocyte differentiation cocktail would increase adiponectin and adipogenic gene expression in bovine satellite cells (BSC). Muscle-derived BSCs were isolated from six, 18-month-old Yanbian Yellow Cattle. The BSC were cultured for 96 h in differentiation medium containing 5 µM ciglitazone (CL), 10 µM ciglitazone (CM), or 20 µM ciglitazone (CH). Control (CON) BSC were cultured only in a differentiation medium (containing 2% horse serum). The presence of myogenin, desmin, and paired box 7 (Pax7) proteins was confirmed in the BSC by immunofluorescence staining. The CL, CM, and CH treatments produced higher concentrations of triacylglycerol and lipid droplet accumulation in myotubes than those of the CON treatment. Ciglitazone treatments significantly increased the relative expression of PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα), C/EBPβ, fatty acid synthase, stearoyl-CoA desaturase, and perilipin 2. Ciglitazone treatments increased gene expression of Pax3 and Pax7 and decreased expression of myogenic differentiation-1, myogenin, myogenic regulatory factor-5, and myogenin-4 (p < 0.01). Adiponectin concentration caused by ciglitazone treatments was significantly greater than CON (p < 0.01). RNA sequencing showed that 281 differentially expressed genes (DEGs) were found in the treatments of ciglitazone. DEGs gene ontology (GO) analysis showed that the top 10 GO enrichment significantly changed the biological processes such as protein trimerization, negative regulation of cell proliferation, adipocytes differentiation, and cellular response to external stimulus. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that DEGs were involved in the p53 signaling pathway, PPAR signaling pathway, biosynthesis of amino acids, tumor necrosis factor signaling pathway, non-alcoholic fatty liver disease, PI3K-Akt signaling pathway, and Wnt signaling pathway. These results indicate that ciglitazone acts as PPARγ agonist, effectively increases the adiponectin concentration and adipogenic gene expression, and stimulates the conversion of BSC to adipocyte-like cells in the absence of adipocyte differentiation cocktail.

주제어

표/그림 (15)

표 Table 1. Forward and reverse primers for Real-time polymerase chain reaction
그림 Fig. 1. Immunofluorescence. The nucleus after DAPI staining was blue, and Pax7 (A), MYOD1 (B) and Desmin (C) were green in the cytoplasm. The original magnification was 40× (scale bars = 200 μm). Results represent three independent experiments. Pax7, Paired box 7; DAPI, 4',6-Diamidino-2-Phenylindole, dihydrochloride.
그림 Fig. 2. Effects of different concentrations of ciglitazone on average cell size and cell viability in BSC after 96-h culture. CON, DMEM + 2% HS; CL, CON + 5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. The same superscript or no superscript on the column means that the difference is not significant (p > 0.05). BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
그림 Fig. 3. Oil red O staining after 96-h incubation of BSC treated with ciglitazone. (A) CON (DMEM + 2% horse serum), (B) CL (CON + 5 μM ciglitazone), (C) CM (CON + 10 μM ciglitazone), (D) CH (CON + 20 μM ciglitazone). Scale bars = 200 μm. BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium.
그림 Fig. 4. Effect of ciglitazone on triacylglycerol and percent lipid droplet area in BSC after 96 h of culture. CON, DMEM + 2% HS; CL, CON + 5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. Error bars are mean ± SE. ^a-dIndicate a significant difference (p < 0.01) within an item compared with undifferentiated cells. The results are representative of six independent experiments. BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle’s medium; HS, horse serum.
그림 Fig. 5. Myogenic gene expression: Pax3, Pax7, MYOD, MYOG, MYF4, and MRF5 gene expression in BSC cultured with ciglitazone in DMEM containing 2% HS after 96 h of incubation. CON, DMEM + 2% HS; CL, CON + 5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. The results of gene expression were consistent with protein expression. The bars are the means ± SE. ^a-dIndicate a significant difference (p < 0.01) within an item compared with undifferentiated cells. The results are representative of six independent experiments. Pax3, Paired box 3; Pax7, Paired box 7; MYOD, myogenic differentiation-1; MYOG, myogenin; MYF4, myogenin-4; MRF5, myogenic regulatory factor-5; BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
그림 Fig. 6. Adipogenic gene expression: PPARγ, C/EBPβ, SREBP1, C/EBPα, ACC, FAS gene expression in BSC cultured with ciglitazone in DMEM containing 2% HS after 96 h of incubation. CON, DMEM + 2% HS; CL, CON + 5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. The results of gene expression were consistent with protein expression. Error bars are the means ± SE. ^a-dIndicate a significant difference (p < 0.01) within an item compared with undifferentiated cells. The results are representative of six separate experiments. PPARγ, peroxisome proliferator-activated receptor gamma; C/EBPß, CCAAT/enhancer-binding protein beta; SREBP1, sterol regulatory element-binding protein-1; C/EBPα, CCAAT/enhancer-binding protein alpha; ACC, acetyl-coenzyme A carboxylase; FAS, fatty acid synthetase; BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
그림 Fig. 7. Gene expression associated with lipid metabolism: CPT1, SCD, AMPKα, LPL, GPR43, FABP4, PLIN2 gene expression in BSC cultured with ciglitazone in DMEM containing 2% HS at 96 h incubation time. CON, DMEM + 2% HS; CL, CON +5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. The results of gene expression were consistent with protein expression. The bars are the means ± SE. ^a-dIndicate a significant difference (p < 0.01) within an item compared with undifferentiated cells. The results are representative of six independent experiments. CPT1, carnitine palmitoyltransferase; SCD, stearoyl-coenzyme A desaturase; AMPKα, adenosine 5'-monophosphate-activated protein kinase; LPL, lipoprotein lipase; GPR43, G protein-coupled receptor-43; FABP4, fatty acid binding protein-4; PLIN2, perilipin-2; BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
그림 Fig. 8. Adiponectin concentration (μg/mL) in media from BSC cultured for 96 h with ciglitazone in DMEM containing 2% HS at 96 h incubation time. CON, DMEM + 2% HS; CL, CON + 5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. The bars are the means ± SE. ^a-dIndicate a significant difference (p < 0.01) within an item compared with undifferentiated cells. The results are representative of six independent experiments. BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
그림 Fig. 9. Differentially Expressed Genes (DEGs) (A) Heatmap for the Figure hierarchical cluster analysis of DEGs after differentiation of BSC in Yanbian Yellow Cattle with different concentrations of ciglitazone, (B) Wayne map and (C) Volcano Plot. Red represents upregulated genes and blue represent downregulated genes. CON, DMEM + 2%HS; CL, CON + 5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
표 Table 2. Number of DEGs after treatment with diferent concentrations of ciglitazone
그림 Fig. 10. Gene Ontology (GO) classification of differentially expressed genes (DEGs) after differentiation of BSC in Yanbian Yellow Cattle with different concentrations of ciglitazone. CON, DMEM + 2% HS; CL, CON + 5 μM ciglitazone; CM, CON + 10 μM ciglitazone; CH, CON + 20 μM ciglitazone. BP, biological process; CC, cellular component; MF, molecular function; BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
그림 Fig. 11. KEGG functional enrichment of transcriptome from skeletal muscle satellite cells of different doses of ciglitazone. CON, DMEM + 2%HS; CON-CL, CON + 5 μM ciglitazone; CON-CM: CON + 10 μM ciglitazone; CON-CH, CON + 20 μM ciglitazone. KEGG, Kyoto Encyclopedia of Genes and Genomes; BSC, bovine satellite cells; DMEM, Dulbecco's modified Eagle's medium; HS, horse serum.
그림 Fig. 12. PPAR signaling pathway regulated by high the concentration of ciglitazone. PPAR, proliferator-activated receptor.
그림 Fig. 13. Distribution of up and downregulated genes enrichment in different Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Pathway nodes (yellow), up-regulated genes (red), and downregulated genes (green) are represented by circles. PPARG, peroxisome proliferator-activated receptor gamma; FABP4, fatty acid binding protein-4; FABP 7, fatty acid binding protein-7; DBI, diazepam binding inhibitor; ANGPTL4, angiopoietin like 4; HMGCS1, hydroxymethylglutaryl-CoA synthase; SCP-2, sterol carrier protein 2; GK; glycerolkinase; GPT2; alanine aminotransferase 2; MMP1; matrix metalloproteinase-1.

AI 본문요약
AI-Helper

제안 방법

The DEGs were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and enrichment analysis of Gene Ontology (GO). KEGG enrichment analysis was to identify the pathways of significant enrichment of DEGs, gene function, genomic information, and functional information. The GO classification includes the following three aspects: biological process (BP), molecular function (MF), and cellular component (CC), which define and describe the functions of selected genes and corresponding proteins.

데이터처리

One-way ANOVA with multiple comparisons test was used to evaluate the statistical significance of differences among treatments. All data are presented as mean ± SEM.

이론/모형

All experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee of Yanbian University using the approval code YBU-20160303.

성능/효과

Besides, the increase in the accumulation of lipid droplets and the concentration of TAG and adiponectin further indicated the regulatory role of PPAR γ in adipogenic transdifferentiation of BSC.
Compared with CON, the CL treatment up-regulated 611 genes and down-regulated 510 genes; the CM treatment up-regulated 565 genes and down-regulated 527 genes; whereas the CH treatment up-regulated 501 genes and down-regulated 435 genes (Table 2). Combined with the analysis of these results of differential expressed genes, BSC treated with CL, CM, and CH had 281 DEGs as shown in the volcano map (Fig. 9A, B, and C).
Expression of AMPK α (p < 0.01) was greater in CL, CM, and CH-treated BSC than in CON BSC, and the CM treatment caused the greatest increase.
In the CH treated BSC, a total of 397 DGEs were enriched in 30 pathways and mainly in the p53 signaling pathway, PPAR signaling pathway, biosynthesis of amino acids, pentose phosphate pathway, and TGF-beta signaling pathway. Genes with up-regulated expression were mainly enriched in the calcium signaling pathway, PPAR signaling pathway, purine metabolism, nicotinate and nicotinamide metabolism, and genes with down-regulated expression were mainly enriched in the biosynthesis of amino acids p53 signaling pathway, glycine, serine, and threonine metabolism, pyrimidine metabolism, and carbon metabolism (Fig. 11 and Supplementary Table S2).
In conclusion, our results support at least partial conversion of BSC to adipocytes by ciglitazone in the absence of an adipocyte differentiation cocktail. Further experiments are needed to elucidate the molecular mechanisms by which PPAR γ affects lipogenesis during the process of adipogenic differentiation of BSC and the regulatory pathways that influence other regulators of lipid production.
adjust, and enriched genes. In the CL treated BSC, KEGG enrichment analysis indicated that a total of 465 DGEs were enriched in 31 pathways and mainly in glycine, serine, and threonine metabolism, tumor necrosis factor (TNF) signaling pathway, and the p53 signaling pathway. Genes with up-regulated expression were mainly enriched in mineral absorption, transcriptional misregulation in cancer, choline metabolism in cancer, glutathione metabolism.
Relative expression of SCD, LPL, GPR43, FABP4, and PLIN2 was dose dependent as the addition level of ciglitazone increased (p < 0.01) (Fig
The CL, CM, and CH treatments increased Pax3 and Pax7 expression and decreased MYOD, MYOG, myogenin-4 (MYF4), and myogenic regulatory factor-5 (MRF5) expression relative to CON (p < 0.01) (Fig
The concentration of cellular TAG, the main component of lipid droplets, was elevated linearly by CL, CM, and CH treatments and, correspondingly, CL, CM, and CH treatments caused a profound increase in the percent area of lipid droplets (Fig. 4) (p < 0.
The expression of MYF4 and MRF5 were the least in the CH-treated BSC (p < 0.01).
There was a dose-response to ciglitazone addition for the expression of adipogenic transcription factors PPAR γ , SREBP1, C/EBP α , C/EBP β , acetyl-coenzyme A carboxylase, and fatty acid synthetase (p < 0.01), and the greatest increase in the expression of these genes, were caused by CH- treated BSC (Fig
Whole-genome RNA-Seq GO analysis and KEGG enrichment analysis of DEGs showed that most DEGs were closely related to cell proliferation, cell differentiation, and cell metabolic processes. PPAR signaling pathway, P53 signaling pathway, Wnt signaling pathway, ribosome, signaling pathway regulating pluripotency of stem cells, TNF signaling pathway, and calcium signaling pathway participate in the adipogenic transdifferentiation process of BSC.

후속연구

Further experiments are needed to elucidate the molecular mechanisms by which PPAR γ affects lipogenesis during the process of adipogenic differentiation of BSC and the regulatory pathways that influence other regulators of lipid production.

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