The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Ji-eun Lee - One of the best experts on this subject based on the ideXlab platform.
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mll3 mll4 associated pagr1 regulates Adipogenesis by controlling induction of c ebpβ and c ebpδ
Molecular and Cellular Biology, 2020Co-Authors: Ji-eun Lee, Chuxia Deng, Young-wook ChoAbstract:Transcription factors C/EBPβ and C/EBPδ are induced within hours after initiation of Adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for Adipogenesis in vivo However, the mechanism that controls the induction of C/EBPβ and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during Adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPβ and C/EBPδ in the early phase of Adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBPβ and C/EBPδ and leads to severe defects in Adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPβ or PPARγ. Finally, the deletion of Pagr1 in Myf5+ precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPβ and C/EBPδ, PAGR1 plays a critical role in Adipogenesis.
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Transcriptional and Epigenomic Regulation of Adipogenesis.
Molecular and cellular biology, 2019Co-Authors: Ji-eun Lee, Hannah Schmidt, Binbin LaiAbstract:Understanding Adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of lineage-determining transcription factors and epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) and C/EBPα are master "adipogenic" transcription factors. In recent years, a growing number of studies have reported the identification of novel transcriptional and epigenomic regulators of Adipogenesis. However, many of these novel regulators have not been validated in adipocyte development in vivo and their working mechanisms are often far from clear. In this minireview, we discuss recent advances in transcriptional and epigenomic regulation of Adipogenesis, with a focus on factors and mechanisms shared by both white Adipogenesis and brown Adipogenesis. Studies on the transcriptional regulation of Adipogenesis highlight the importance of investigating adipocyte differentiation in vivo rather than drawing conclusions based on knockdown experiments in cell culture. Advances in understanding of epigenomic regulation of Adipogenesis have revealed critical roles of histone methylation/demethylation, histone acetylation/deacetylation, chromatin remodeling, DNA methylation, and microRNAs in adipocyte differentiation. We also discuss future research directions that may help identify novel factors and mechanisms regulating Adipogenesis.
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mll3 mll4 are required for cbp p300 binding on enhancers and super enhancer formation in brown Adipogenesis
Nucleic Acids Research, 2017Co-Authors: Younghoon Jang, Ji-eun Lee, Binbin Lai, Lifeng Wang, Weiqun PengAbstract:Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes in cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors (EBF2, C/EBPβ, C/EBPα, PPARγ), coactivator MED1, RNA polymerase II, as well as epigenome (H3K4me1/2/3, H3K9me2, H3K27me3, H3K36me3, H3K27ac), transcriptome and chromatin opening during Adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT). We show that MLL4 and CBP drive the dynamic enhancer epigenome, which correlates with the dynamic transcriptome. MLL3/MLL4 are required for CBP/p300 binding on enhancers activated during Adipogenesis. Further, MLL4 and CBP identify super-enhancers (SEs) of Adipogenesis and that MLL3/MLL4 are required for SE formation. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed SEs of genes fully activated in BAT such as Ucp1. Comparison of MLL4-defined SEs in brown and white Adipogenesis identifies brown-specific SE-associated genes that could be involved in BAT functions. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers and suggest that enhancer-priming by MLL3/MLL4 followed by enhancer-activation by CBP/p300 sequentially shape dynamic enhancer landscapes during cell differentiation. Our data also provide a rich resource for understanding epigenomic regulation of brown Adipogenesis.
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Transcriptional and epigenetic regulation of PPARγ expression during Adipogenesis.
Cell & bioscience, 2014Co-Authors: Ji-eun LeeAbstract:The nuclear receptor PPARγ is a master regulator of Adipogenesis. PPARγ is highly expressed in adipose tissues and its expression is markedly induced during Adipogenesis. In this review, we describe the current knowledge, as well as future directions, on transcriptional and epigenetic regulation of PPARγ expression during Adipogenesis. Investigating the molecular mechanisms that control PPARγ expression during Adipogenesis is critical for understanding the development of white and brown adipose tissues, as well as pathological conditions such as obesity and diabetes. The robust induction of PPARγ expression during Adipogenesis also serves as an excellent model system for studying transcriptional and epigenetic regulation of cell-type-specific gene expression.
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Histone H3K9 methyltransferase G9a represses PPARγ expression and Adipogenesis
The EMBO journal, 2012Co-Authors: Lifeng Wang, Ji-eun Lee, Anne Baldridge, Sean Grullon, Weiqun PengAbstract: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 selectively 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 the early adipogenic transcription factor C/EBPβ 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.
Richard P Phipps - One of the best experts on this subject based on the ideXlab platform.
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thy1 cd90 expression is regulated by dna methylation during Adipogenesis
The FASEB Journal, 2019Co-Authors: Elissa M Flores, Collynn F Woeller, Megan L Falsetta, Martha Susiarjo, Richard P PhippsAbstract:The obesity epidemic is developing into the most costly health problem facing the world. Obesity, characterized by excessive Adipogenesis and enlarged adipocytes, promotes morbidities, such as diabetes, cardiovascular disease, and cancer. Regulation of Adipogenesis is critical to our understanding of how fat cell formation causes obesity and associated health problems. Thy1 (also called CD90), a widely used stem cell marker, blocks Adipogenesis and reduces lipid accumulation. Thy1-knockout mice are prone to diet-induced obesity. Although the importance of Thy1 in Adipogenesis and obesity is now evident, how its expression is regulated is not. We hypothesized that DNA methylation has a role in promoting Adipogenesis and affects Thy1 expression. Using the methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC), we investigated whether DNA methylation alters Thy1 expression during Adipogenesis in both mouse 3T3-L1 preadipocytes and mouse mesenchymal stem cells. Thy1 protein and mRNA levels were decreased dramatically during Adipogenesis. However, 5-aza-dC treatment prevented that phenomenon. Methylation-sensitive pyrosequencing analysis showed that CpG sites at the Thy1 locus have increased methylation during Adipogenesis, as well as increased methylation in adipose tissue from diet-induced obese mice. These new findings highlight the potential role of Thy1 and DNA methylation in Adipogenesis and obesity.-Flores, E. M., Woeller, C. F., Falsetta, M. L., Susiarjo, M., Phipps, R. P. Thy1 (CD90) expression is regulated by DNA methylation during Adipogenesis.
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thy1 cd90 expression is regulated by dna methylation during Adipogenesis
bioRxiv, 2018Co-Authors: Elissa M Flores, Collynn F Woeller, Megan L Falsetta, Martha Susiarjo, Richard P PhippsAbstract:The obesity epidemic is developing into the most costly health problem facing the world. Obesity, characterized by excessive Adipogenesis and enlarged adipocytes, promotes morbidities such as diabetes, cardiovascular disease and cancer. Regulation of Adipogenesis is critical to our understanding of how fat cell formation causes obesity and associated health problems. Thy1 (also called CD90), a widely used stem cell marker, blocks Adipogenesis and reduces lipid accumulation. Thy1 knockout-mice are prone to diet-induced obesity. While the importance of Thy1 in Adipogenesis and obesity is now evident, how its expression is regulated is not. We hypothesized that DNA methylation plays a role in promoting Adipogenesis and affects Thy1 expression. Using the methylation inhibitor 5-aza-2-deoxycytidine (5-aza-dC), we investigated whether DNA methylation alters Thy1 expression during Adipogenesis in both mouse 3T3-L1 pre-adipocytes and mouse mesenchymal stem cells. Thy1 protein and mRNA levels were decreased dramatically during Adipogenesis. However, 5-aza-dC treatment prevented this phenomenon. Pyrosequencing analysis shows that the CpG sites at the Thy1 locus are methylated during Adipogenesis. These new findings highlight the potential role of Thy1 and DNA methylation in Adipogenesis and obesity.
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editor s highlight thy1 cd90 expression is reduced by the environmental chemical tetrabromobisphenol a to promote Adipogenesis through induction of microrna 103
Toxicological Sciences, 2017Co-Authors: Collynn F Woeller, Elissa M Flores, Stephen J Pollock, Richard P PhippsAbstract:Environmental chemicals termed "obesogens" disrupt the endocrine system to promote Adipogenesis and obesity. Tetrabromobisphenol-A (TBBPA) has been reported to increase Adipogenesis; however, the mechanism(s) of action are unclear. Thy1 (CD90) is a glycophosphatidylinositol-anchored membrane protein that serves as a marker for stem cells and also plays an important role in regulating Adipogenesis and obesity. We investigated whether or not TBBPA promotes Adipogenesis in human and mouse cells by reducing Thy1 levels. We further sought to identify the molecular mechanism(s) whereby TBBPA targets Thy1 expression. Mouse and human cells were exposed to TBBPA, and Thy1 expression was analyzed using flow cytometry, Western blotting, and qPCR. We tested whether microRNAs predicted to target Thy1 (miR-103 and miR-107) were upregulated by TBBPA using quantitative PCR assays. We also determined if Thy1 mRNA was a bona fide miR-103/107 target. Our results show that Thy1 expression was reduced in both human and mouse cells after exposure to TBBPA. Both Thy1 mRNA and protein levels were decreased by low-dose TBBPA exposure. TBBPA reduced Thy1 levels and further increased Adipogenesis when an adipogenic medium was used. Mechanistically, we show that miR-103 and miR-107 are induced by TBBPA and that miR-103 targets Thy1 to reduce its expression. Our results reveal for the first time that Thy1 is a target of TBBPA. Furthermore, our data support the concept that Thy1 is a key marker targeted by environmental chemicals that promote Adipogenesis and obesity.
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orbital fibroblasts from thyroid eye disease patients differ in proliferative and adipogenic responses depending on disease subtype
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Collynn F Woeller, Richard P Phipps, Ajay E Kuriyan, Charles W Oloughlin, Steven E FeldonAbstract:PURPOSE Thyroid eye disease (TED) patients are classified as type I (predominantly fat compartment enlargement) or type II (predominantly extraocular muscle enlargement) based on orbital imaging. Orbital fibroblasts (OFs) can be driven to proliferate or differentiate into adipocytes in vitro. We tested the hypothesis that type I OFs undergo more Adipogenesis than type II OFs, whereas type II OFs proliferate more than type I OFs. We also examined the effect of cyclooxygenase (COX) inhibitors on OF Adipogenesis and proliferation. METHODS Type I, type II, and non-TED OFs were treated with transforming growth factor-beta (TGFβ) to induce proliferation and with 15-deoxy-Δ(-12,14)-prostaglandin J2 (15d-PGJ2) to induce Adipogenesis. Proliferation was measured using the [(3)H]thymidine assay, and Adipogenesis was measured using the AdipoRed assay, Oil Red O staining, and flow cytometry. The effect of COX inhibition on Adipogenesis and proliferation was also studied. RESULTS Type II OFs incorporated 1.7-fold more [(3)H]thymidine than type I OFs (P < 0.05). Type I OFs accumulated 4.8-fold more lipid than type II OFs (P < 0.05) and 12.6-fold more lipid than non-TED OFs (P < 0.05). Oil Red O staining and flow cytometry also demonstrated increased Adipogenesis in type I OFs compared to type II and non-TED OFs. Cyclooxygenase inhibition significantly decreased proliferation and Adipogenesis in type II OFs, but not type I OFs. CONCLUSIONS We have demonstrated that OFs from TED patients have heterogeneous responses to proproliferative and proadipogenic stimulators in vitro in a manner that corresponds to their different clinical manifestations. Furthermore, we demonstrated a differential effect of COX inhibitors on type I and type II OF proliferation and Adipogenesis.
Marcelo Lima Ribeiro - One of the best experts on this subject based on the ideXlab platform.
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effects of yerba mate a plant extract formulation ygd and resveratrol in 3t3 l1 Adipogenesis
Molecules, 2014Co-Authors: Juliana Carvalho Santos, Alessandra Gambero, Erica Martins Ferreira Gotardo, Mitsue T Brianti, Mahmood Piraee, Marcelo Lima RibeiroAbstract:We aimed to evaluate the in vitro effects of yerba mate, YGD (a herbal preparation containing yerba mate, guarana and damiana), and resveratrol on Adipogenesis. The anti-adipogenic effects of yerba mate, YGD, resveratrol and YGD + resveratrol and yerba mate + resveratrol combinations were evaluated in 3T3-L1 cells by Oil Red staining, cellular triglyceride content, and PCR quantitative array. The results demonstrated that all of the tested compounds inhibited Adipogenesis. Yerba mate extract significantly down-regulated the expression of genes that play an important role in regulating Adipogenesis, such as Adig, Axin, Cebpa, Fgf10, Lep, Lpl, and Pparγ2. In addition, these genes, YGD also repressed Bmp2, Ccnd1, Fasn, and Srebf1. Resveratrol also modulated the expression of Adig, Bmp2, Ccnd1, C/EBPα, Fasn, Fgf10, Lep, Lpl, and Pparγ2. Moreover, resveratrol repressed Cebpb, Cdk4, Fgf2, and Klf15. The yerba mate extract and YGD up-regulated the expression of genes involved in inhibiting Adipogenesis, such as Dlk-1, Klf2, and Ucp1. Resveratrol also induced the expression of Klf2 and Ucp1. In addition resveratrol modulated the Ddit3, Foxo1, Sirt1, and Sirt2. The combined effects of these compounds on gene expression showed similar results observed from individual treatments. Our data indicates that the synergy between the compounds favors the inhibition of Adipogenesis.
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the in vitro and in vivo effects of yerba mate ilex paraguariensis extract on Adipogenesis
Food Chemistry, 2013Co-Authors: Demetrius Paiva Arcari, Alessandra Gambero, Marcelo Lima Ribeiro, Juliana Carvalho SantosAbstract:The aim of this study was to evaluate the effects of yerba mate extract and its principal bioactive compounds on Adipogenesis. The anti-adipogenic effects of yerba mate, chlorogenic acid, quercetin and rutin were evaluated in 3T3-L1 cells using a PCR array. The results obtained in vitro were validated in vivo in a high-fat diet-induced model of obesity. The in vitro and in vivo results demonstrated that yerba mate extract down-regulated the expression of genes that regulate Adipogenesis, such as Creb-1and C/EBPα, and the extract up-regulated the expression of genes related to the inhibition of Adipogenesis, including Dlk1, Gata2, Gata3, Klf2, Lrp5, Pparγ2, Sfrp1, Tcf7l2, Wnt10b, and Wnt3a. In summary, it was demonstrated that yerba mate and its bioactive compounds regulate the expression of genes related to in vitro Adipogenesis. Furthermore, yerba mate might regulate Adipogenesis through the Wnt pathway.
Chuxia Deng - One of the best experts on this subject based on the ideXlab platform.
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mll3 mll4 associated pagr1 regulates Adipogenesis by controlling induction of c ebpβ and c ebpδ
Molecular and Cellular Biology, 2020Co-Authors: Ji-eun Lee, Chuxia Deng, Young-wook ChoAbstract:Transcription factors C/EBPβ and C/EBPδ are induced within hours after initiation of Adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for Adipogenesis in vivo However, the mechanism that controls the induction of C/EBPβ and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during Adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPβ and C/EBPδ in the early phase of Adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBPβ and C/EBPδ and leads to severe defects in Adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPβ or PPARγ. Finally, the deletion of Pagr1 in Myf5+ precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPβ and C/EBPδ, PAGR1 plays a critical role in Adipogenesis.
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sirt6 is essential for adipocyte differentiation by regulating mitotic clonal expansion
Cell Reports, 2017Co-Authors: Qiang Chen, Cuiying Xiao, Ruihong Wang, Xiaoling Xu, Huiyan Lu, Weiping Chen, Chuxia DengAbstract:Summary Preadipocytes initiate differentiation into adipocytes through a cascade of events. Mitotic clonal expansion, as one of the earliest events, is essential for Adipogenesis. However, the underlying mechanisms that regulate mitotic clonal expansion remain elusive. SIRT6 is a member of the evolutionarily conserved sirtuin family of nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases. Here, we show that SIRT6 deficiency in preadipocytes blocks their Adipogenesis. Analysis of gene expression during Adipogenesis reveals that KIF5C, which belongs to the kinesin family, is negatively regulated by SIRT6. Furthermore, we show that KIF5C is a negative factor for Adipogenesis through interacting with CK2α′, a catalytic subunit of CK2. This interaction blocks CK2α′ nuclear translocation and CK2 kinase activity and inhibits mitotic clonal expansion during Adipogenesis. These findings reveal a crucial role of SIRT6 in Adipogenesis and provide potential therapeutic targets for obesity.
Collynn F Woeller - One of the best experts on this subject based on the ideXlab platform.
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thy1 cd90 expression is regulated by dna methylation during Adipogenesis
The FASEB Journal, 2019Co-Authors: Elissa M Flores, Collynn F Woeller, Megan L Falsetta, Martha Susiarjo, Richard P PhippsAbstract:The obesity epidemic is developing into the most costly health problem facing the world. Obesity, characterized by excessive Adipogenesis and enlarged adipocytes, promotes morbidities, such as diabetes, cardiovascular disease, and cancer. Regulation of Adipogenesis is critical to our understanding of how fat cell formation causes obesity and associated health problems. Thy1 (also called CD90), a widely used stem cell marker, blocks Adipogenesis and reduces lipid accumulation. Thy1-knockout mice are prone to diet-induced obesity. Although the importance of Thy1 in Adipogenesis and obesity is now evident, how its expression is regulated is not. We hypothesized that DNA methylation has a role in promoting Adipogenesis and affects Thy1 expression. Using the methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC), we investigated whether DNA methylation alters Thy1 expression during Adipogenesis in both mouse 3T3-L1 preadipocytes and mouse mesenchymal stem cells. Thy1 protein and mRNA levels were decreased dramatically during Adipogenesis. However, 5-aza-dC treatment prevented that phenomenon. Methylation-sensitive pyrosequencing analysis showed that CpG sites at the Thy1 locus have increased methylation during Adipogenesis, as well as increased methylation in adipose tissue from diet-induced obese mice. These new findings highlight the potential role of Thy1 and DNA methylation in Adipogenesis and obesity.-Flores, E. M., Woeller, C. F., Falsetta, M. L., Susiarjo, M., Phipps, R. P. Thy1 (CD90) expression is regulated by DNA methylation during Adipogenesis.
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thy1 cd90 expression is regulated by dna methylation during Adipogenesis
bioRxiv, 2018Co-Authors: Elissa M Flores, Collynn F Woeller, Megan L Falsetta, Martha Susiarjo, Richard P PhippsAbstract:The obesity epidemic is developing into the most costly health problem facing the world. Obesity, characterized by excessive Adipogenesis and enlarged adipocytes, promotes morbidities such as diabetes, cardiovascular disease and cancer. Regulation of Adipogenesis is critical to our understanding of how fat cell formation causes obesity and associated health problems. Thy1 (also called CD90), a widely used stem cell marker, blocks Adipogenesis and reduces lipid accumulation. Thy1 knockout-mice are prone to diet-induced obesity. While the importance of Thy1 in Adipogenesis and obesity is now evident, how its expression is regulated is not. We hypothesized that DNA methylation plays a role in promoting Adipogenesis and affects Thy1 expression. Using the methylation inhibitor 5-aza-2-deoxycytidine (5-aza-dC), we investigated whether DNA methylation alters Thy1 expression during Adipogenesis in both mouse 3T3-L1 pre-adipocytes and mouse mesenchymal stem cells. Thy1 protein and mRNA levels were decreased dramatically during Adipogenesis. However, 5-aza-dC treatment prevented this phenomenon. Pyrosequencing analysis shows that the CpG sites at the Thy1 locus are methylated during Adipogenesis. These new findings highlight the potential role of Thy1 and DNA methylation in Adipogenesis and obesity.
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editor s highlight thy1 cd90 expression is reduced by the environmental chemical tetrabromobisphenol a to promote Adipogenesis through induction of microrna 103
Toxicological Sciences, 2017Co-Authors: Collynn F Woeller, Elissa M Flores, Stephen J Pollock, Richard P PhippsAbstract:Environmental chemicals termed "obesogens" disrupt the endocrine system to promote Adipogenesis and obesity. Tetrabromobisphenol-A (TBBPA) has been reported to increase Adipogenesis; however, the mechanism(s) of action are unclear. Thy1 (CD90) is a glycophosphatidylinositol-anchored membrane protein that serves as a marker for stem cells and also plays an important role in regulating Adipogenesis and obesity. We investigated whether or not TBBPA promotes Adipogenesis in human and mouse cells by reducing Thy1 levels. We further sought to identify the molecular mechanism(s) whereby TBBPA targets Thy1 expression. Mouse and human cells were exposed to TBBPA, and Thy1 expression was analyzed using flow cytometry, Western blotting, and qPCR. We tested whether microRNAs predicted to target Thy1 (miR-103 and miR-107) were upregulated by TBBPA using quantitative PCR assays. We also determined if Thy1 mRNA was a bona fide miR-103/107 target. Our results show that Thy1 expression was reduced in both human and mouse cells after exposure to TBBPA. Both Thy1 mRNA and protein levels were decreased by low-dose TBBPA exposure. TBBPA reduced Thy1 levels and further increased Adipogenesis when an adipogenic medium was used. Mechanistically, we show that miR-103 and miR-107 are induced by TBBPA and that miR-103 targets Thy1 to reduce its expression. Our results reveal for the first time that Thy1 is a target of TBBPA. Furthermore, our data support the concept that Thy1 is a key marker targeted by environmental chemicals that promote Adipogenesis and obesity.
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orbital fibroblasts from thyroid eye disease patients differ in proliferative and adipogenic responses depending on disease subtype
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Collynn F Woeller, Richard P Phipps, Ajay E Kuriyan, Charles W Oloughlin, Steven E FeldonAbstract:PURPOSE Thyroid eye disease (TED) patients are classified as type I (predominantly fat compartment enlargement) or type II (predominantly extraocular muscle enlargement) based on orbital imaging. Orbital fibroblasts (OFs) can be driven to proliferate or differentiate into adipocytes in vitro. We tested the hypothesis that type I OFs undergo more Adipogenesis than type II OFs, whereas type II OFs proliferate more than type I OFs. We also examined the effect of cyclooxygenase (COX) inhibitors on OF Adipogenesis and proliferation. METHODS Type I, type II, and non-TED OFs were treated with transforming growth factor-beta (TGFβ) to induce proliferation and with 15-deoxy-Δ(-12,14)-prostaglandin J2 (15d-PGJ2) to induce Adipogenesis. Proliferation was measured using the [(3)H]thymidine assay, and Adipogenesis was measured using the AdipoRed assay, Oil Red O staining, and flow cytometry. The effect of COX inhibition on Adipogenesis and proliferation was also studied. RESULTS Type II OFs incorporated 1.7-fold more [(3)H]thymidine than type I OFs (P < 0.05). Type I OFs accumulated 4.8-fold more lipid than type II OFs (P < 0.05) and 12.6-fold more lipid than non-TED OFs (P < 0.05). Oil Red O staining and flow cytometry also demonstrated increased Adipogenesis in type I OFs compared to type II and non-TED OFs. Cyclooxygenase inhibition significantly decreased proliferation and Adipogenesis in type II OFs, but not type I OFs. CONCLUSIONS We have demonstrated that OFs from TED patients have heterogeneous responses to proproliferative and proadipogenic stimulators in vitro in a manner that corresponds to their different clinical manifestations. Furthermore, we demonstrated a differential effect of COX inhibitors on type I and type II OF proliferation and Adipogenesis.