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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

Synergism of cPGI2 signaling during progenitor activation and adipocyte maturation for the induction of thermogenic marker genes. Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media for 8 days. cPGI2 was included in the media as indicated by the gray bars. Three hours before harvest, cells were cultured ± NE. RNA expression of Ucp1(A) and Cidea(B) was analyzed by qRT-PCR [* and # indicate Tukey p < 0.05 for the respective group vs. Control (0–8 days) and vs. cPGI2 (0–8 days), respectively, n = 3].
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Figure 3: Synergism of cPGI2 signaling during progenitor activation and adipocyte maturation for the induction of thermogenic marker genes. Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media for 8 days. cPGI2 was included in the media as indicated by the gray bars. Three hours before harvest, cells were cultured ± NE. RNA expression of Ucp1(A) and Cidea(B) was analyzed by qRT-PCR [* and # indicate Tukey p < 0.05 for the respective group vs. Control (0–8 days) and vs. cPGI2 (0–8 days), respectively, n = 3].

Mentions: Given the late upregulation of Ucp1 expression by cPGI2, we sought to define the role of late vs. early cPGI2 signaling. To define the differentiation time window in which cPGI2 stimulation promotes beige/brite differentiation, we restricted the duration of cPGI2 treatment (Figures 3A,B). Neither the early nor the late cPGI2 stimulation was sufficient to induce the full activation of Ucp1 and Cidea expression. Intriguingly, early cPGI2 signaling during progenitor commitment (day 0–2) synergized with late cPGI2 stimulation during maturation (day 3–8) in a non-additive manner, highlighting an important role during progenitor activation.


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)

Synergism of cPGI2 signaling during progenitor activation and adipocyte maturation for the induction of thermogenic marker genes. Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media for 8 days. cPGI2 was included in the media as indicated by the gray bars. Three hours before harvest, cells were cultured ± NE. RNA expression of Ucp1(A) and Cidea(B) was analyzed by qRT-PCR [* and # indicate Tukey p < 0.05 for the respective group vs. Control (0–8 days) and vs. cPGI2 (0–8 days), respectively, n = 3].
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4538297&req=5

Figure 3: Synergism of cPGI2 signaling during progenitor activation and adipocyte maturation for the induction of thermogenic marker genes. Lin−CD29+CD34+Sca-1+ cells were cultured in adipogenic media for 8 days. cPGI2 was included in the media as indicated by the gray bars. Three hours before harvest, cells were cultured ± NE. RNA expression of Ucp1(A) and Cidea(B) was analyzed by qRT-PCR [* and # indicate Tukey p < 0.05 for the respective group vs. Control (0–8 days) and vs. cPGI2 (0–8 days), respectively, n = 3].
Mentions: Given the late upregulation of Ucp1 expression by cPGI2, we sought to define the role of late vs. early cPGI2 signaling. To define the differentiation time window in which cPGI2 stimulation promotes beige/brite differentiation, we restricted the duration of cPGI2 treatment (Figures 3A,B). Neither the early nor the late cPGI2 stimulation was sufficient to induce the full activation of Ucp1 and Cidea expression. Intriguingly, early cPGI2 signaling during progenitor commitment (day 0–2) synergized with late cPGI2 stimulation during maturation (day 3–8) in a non-additive manner, highlighting an important role during progenitor activation.

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