Transcriptional Pathways in cPGI2-Induced Adipocyte Progenitor Activation for Browning

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.

Cold-Induced Browning of Inguinal White Adipose Tissue Is Independent of Adipose Tissue Cyclooxygenase-2

“…Aside from these limitations, the physiological relevance of an undocumented but presumably substantially augmented (Bol et al, 2002) and sustained increase in prostaglandin biosynthesis in COX-2 overexpressing mice is, at best, arguable. Similar constraints apply to the reports that micromolar concentrations of carbaprostacyclin, a synthetic analog of the COX-2 product, prostacyclin, promote browning of adipocytes in in vitro cell-culture models (Bayindir et al, 2015; Ghandour et al, 2016). Endogenous prostanoids, such as prostacyclin, are formed transiently and, at femtomolar to picomolar quantities, to act locally (FitzGerald et al, 1981).…”

Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis

“…Adipose progenitors were isolated by magnetic-activated cell sorting (MACS) approach, as previously described (17,18). Briefly, the SVF …”

“…Sorting of adipose tissue cell populations was performed as previously described (18). Briefly, adipocytes and SVF were separated by centrifugation of digested and strained adipose tissue.…”

“…Acquisition and derivation of mean average signal for each probe on the Illumina Mouse Sentrix-6 BeadChip arrays (Illumina) were performed as previously described (18). Intensity values were normalized by quantile normalization using Chipster Software (CSC).…”

Acide arachidonique et prostaglandines : impact sur la formation des adipocytes blancs, bruns et brites/beiges

“…3) [44,46]. L'engagement des préadipocytes dans la voie de différenciation en adipocytes brites serait dépendante du récepteur IP et pourrait mettre en jeu des réorganisations du cytosquelette et/ou de la chromatine [46,50]. De même, l'effet de cPGI2 sur la conversion des adipocytes blancs en brites est dépendant des voies faisant intervenir des variations des niveaux d'AMPc [44].…”