Transcriptional Pathways in cPGI2-Induced Adipocyte Progenitor Activation for Browning.
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.
DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center , Heidelberg , Germany.
Irem
I
Bayindir
DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center , Heidelberg , Germany.
Rohollah
R
Babaeikelishomi
University of Toulouse (UPS) , Toulouse , France ; Laboratoire de Biologie Moléculaire des Eucaryotes, Centre national de la recherche scientifique , Toulouse , France.
Silvia
S
Kocanova
DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center , Heidelberg , Germany ; Department of Life Sciences, University of Coimbra , Coimbra , Portugal.
Isabel Sofia
IS
Sousa
DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center , Heidelberg , Germany.
Sarah
S
Lerch
Miltenyi Biotec GmbH , Bergisch Gladbach , Germany.
Olaf
O
Hardt
Miltenyi Biotec GmbH , Bergisch Gladbach , Germany.
Stefan
S
Wild
Miltenyi Biotec GmbH , Bergisch Gladbach , Germany.
Andreas
A
Bosio
University of Toulouse (UPS) , Toulouse , France ; Laboratoire de Biologie Moléculaire des Eucaryotes, Centre national de la recherche scientifique , Toulouse , France.
Kerstin
K
Bystricky
Helmholtz Center Munich, Institute for Diabetes and Cancer IDC , Neuherberg , Germany ; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital , Heidelberg , Germany.
Stephan
S
Herzig
DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center , Heidelberg , Germany.
Alexandros
A
Vegiopoulos
PGI2; adipocyte cell model; adipocyte progenitors; adipose tissue remodeling; beige/brite differentiation; nuclear localization; prostacyclin