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Transcriptional Pathways in cPGI2-Induced Adipocyte Progenitor Activation for Browning.

Bayindir I, Babaeikelishomi R, Kocanova S, Sousa IS, Lerch S, Hardt O, Wild S, Bosio A, Bystricky K, Herzig S, Vegiopoulos A - Front Endocrinol (Lausanne) (2015)

Bottom Line: We demonstrate the specific and broad induction of thermogenic gene expression by PGI2 signaling in the absence of lineage conversion, and reveal the previously unidentified nuclear relocalization of the Ucp1 gene locus in association with transcriptional activation.By profiling the time course of the progenitor response, we show that PGI2 signaling promoted progenitor cell activation through cell cycle and adhesion pathways prior to metabolic maturation toward an oxidative cell phenotype.Our results highlight the importance of core progenitor activation pathways for the recruitment of thermogenic cells and provide a resource for further mechanistic investigation.

View Article: PubMed Central - PubMed

Affiliation: DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center , Heidelberg , Germany.

ABSTRACT
De novo formation of beige/brite adipocytes from progenitor cells contributes to the thermogenic adaptation of adipose tissue and holds great potential for the therapeutic remodeling of fat as a treatment for obesity. Despite the recent identification of several factors regulating browning of white fat, there is a lack of physiological cell models for the mechanistic investigation of progenitor-mediated beige/brite differentiation. We have previously revealed prostacyclin (PGI2) as one of the few known endogenous extracellular mediators promoting de novo beige/brite formation by relaying β-adrenergic stimulation to the progenitor level. Here, we present a cell model based on murine primary progenitor cells defined by markers previously shown to be relevant for in vivo browning, including a simplified isolation procedure. We demonstrate the specific and broad induction of thermogenic gene expression by PGI2 signaling in the absence of lineage conversion, and reveal the previously unidentified nuclear relocalization of the Ucp1 gene locus in association with transcriptional activation. By profiling the time course of the progenitor response, we show that PGI2 signaling promoted progenitor cell activation through cell cycle and adhesion pathways prior to metabolic maturation toward an oxidative cell phenotype. Our results highlight the importance of core progenitor activation pathways for the recruitment of thermogenic cells and provide a resource for further mechanistic investigation.

No MeSH data available.


Related in: MedlinePlus

Progenitor activation by cPGI2 precedes metabolic differentiation. (A) Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media ± cPGI2 for the indicated times, at which RNA was obtained for expression profiling with Illumina beadchip arrays (n = 3). GSEA was performed at each time point (cPGI2 vs. Control) with the KEGG pathway gene set collection. The enrichment scores of the indicated gene sets related to progenitor activation (red) or metabolic maturation (black) are plotted. Closed markers indicate significance (FDR q < 0.05). (B) Schematic summary of the kinetics of progenitor cell responses to cPGI2 as detected by gene expression assays, GSEA and EdU incorporation analysis.
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Figure 5: Progenitor activation by cPGI2 precedes metabolic differentiation. (A) Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media ± cPGI2 for the indicated times, at which RNA was obtained for expression profiling with Illumina beadchip arrays (n = 3). GSEA was performed at each time point (cPGI2 vs. Control) with the KEGG pathway gene set collection. The enrichment scores of the indicated gene sets related to progenitor activation (red) or metabolic maturation (black) are plotted. Closed markers indicate significance (FDR q < 0.05). (B) Schematic summary of the kinetics of progenitor cell responses to cPGI2 as detected by gene expression assays, GSEA and EdU incorporation analysis.

Mentions: In order to determine the temporal order of progenitor responses to cPGI2 and their relation to the metabolic differentiation toward the oxidative thermogenic phenotype, we performed GSEA across the time course of cPGI2 treatment, i.e., cPGI2 vs. Control at each time point (Figure 5A). Intriguingly, the cytoskeletal and adhesion changes as well as the transient cell cycle activation by cPGI2 preceded the upregulation of oxidative pathways including Ppar target genes. Taken together, our findings suggest that the synergism between early and late cPGI2 signaling results from the early activation of progenitors and priming for the later induction of oxidative/thermogenic genes by cPGI2 (Figure 5B).


Transcriptional Pathways in cPGI2-Induced Adipocyte Progenitor Activation for Browning.

Bayindir I, Babaeikelishomi R, Kocanova S, Sousa IS, Lerch S, Hardt O, Wild S, Bosio A, Bystricky K, Herzig S, Vegiopoulos A - Front Endocrinol (Lausanne) (2015)

Progenitor activation by cPGI2 precedes metabolic differentiation. (A) Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media ± cPGI2 for the indicated times, at which RNA was obtained for expression profiling with Illumina beadchip arrays (n = 3). GSEA was performed at each time point (cPGI2 vs. Control) with the KEGG pathway gene set collection. The enrichment scores of the indicated gene sets related to progenitor activation (red) or metabolic maturation (black) are plotted. Closed markers indicate significance (FDR q < 0.05). (B) Schematic summary of the kinetics of progenitor cell responses to cPGI2 as detected by gene expression assays, GSEA and EdU incorporation analysis.
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Related In: Results  -  Collection

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Figure 5: Progenitor activation by cPGI2 precedes metabolic differentiation. (A) Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media ± cPGI2 for the indicated times, at which RNA was obtained for expression profiling with Illumina beadchip arrays (n = 3). GSEA was performed at each time point (cPGI2 vs. Control) with the KEGG pathway gene set collection. The enrichment scores of the indicated gene sets related to progenitor activation (red) or metabolic maturation (black) are plotted. Closed markers indicate significance (FDR q < 0.05). (B) Schematic summary of the kinetics of progenitor cell responses to cPGI2 as detected by gene expression assays, GSEA and EdU incorporation analysis.
Mentions: In order to determine the temporal order of progenitor responses to cPGI2 and their relation to the metabolic differentiation toward the oxidative thermogenic phenotype, we performed GSEA across the time course of cPGI2 treatment, i.e., cPGI2 vs. Control at each time point (Figure 5A). Intriguingly, the cytoskeletal and adhesion changes as well as the transient cell cycle activation by cPGI2 preceded the upregulation of oxidative pathways including Ppar target genes. Taken together, our findings suggest that the synergism between early and late cPGI2 signaling results from the early activation of progenitors and priming for the later induction of oxidative/thermogenic genes by cPGI2 (Figure 5B).

Bottom Line: We demonstrate the specific and broad induction of thermogenic gene expression by PGI2 signaling in the absence of lineage conversion, and reveal the previously unidentified nuclear relocalization of the Ucp1 gene locus in association with transcriptional activation.By profiling the time course of the progenitor response, we show that PGI2 signaling promoted progenitor cell activation through cell cycle and adhesion pathways prior to metabolic maturation toward an oxidative cell phenotype.Our results highlight the importance of core progenitor activation pathways for the recruitment of thermogenic cells and provide a resource for further mechanistic investigation.

View Article: PubMed Central - PubMed

Affiliation: DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center , Heidelberg , Germany.

ABSTRACT
De novo formation of beige/brite adipocytes from progenitor cells contributes to the thermogenic adaptation of adipose tissue and holds great potential for the therapeutic remodeling of fat as a treatment for obesity. Despite the recent identification of several factors regulating browning of white fat, there is a lack of physiological cell models for the mechanistic investigation of progenitor-mediated beige/brite differentiation. We have previously revealed prostacyclin (PGI2) as one of the few known endogenous extracellular mediators promoting de novo beige/brite formation by relaying β-adrenergic stimulation to the progenitor level. Here, we present a cell model based on murine primary progenitor cells defined by markers previously shown to be relevant for in vivo browning, including a simplified isolation procedure. We demonstrate the specific and broad induction of thermogenic gene expression by PGI2 signaling in the absence of lineage conversion, and reveal the previously unidentified nuclear relocalization of the Ucp1 gene locus in association with transcriptional activation. By profiling the time course of the progenitor response, we show that PGI2 signaling promoted progenitor cell activation through cell cycle and adhesion pathways prior to metabolic maturation toward an oxidative cell phenotype. Our results highlight the importance of core progenitor activation pathways for the recruitment of thermogenic cells and provide a resource for further mechanistic investigation.

No MeSH data available.


Related in: MedlinePlus