Fat cells (adipocytes) develop from adipocyte precursor cells (preadipocytes) that themselves derive from mesenchymal progenitors. Although the events controlling preadipocyte differentiation into mature adipocytes have been largely explored, the mechanisms that direct mesenchymal progenitors down the adipocyte pathway remain unknown. Similarly, although adipocytes are generally thought to derive from mesoderm, key information is lacking regarding the origin and the development of the adipose tissue during embryogenesis. The aim of this study was to gain insight into the ontogeny of fat cells, both in mouse embryonic stem (mES) cell-derived cultures and during normal development. We first used genetically engineered mES cells to produce and select ES cellderived neuroepithelial progenitors and showed that neuroectoderm, rather than mesoderm, may be a source of adipocytes in mES cell-derived cultures. We then used primary and secondary cultures of developing quail neural crest (NC) cells to demonstrate that NC cells are able, upon stimulation with defined factors, to differentiate into adipocytes, thus providing a powerful system to study the earliest stages of adipocyte differentiation. Finally, we mapped NC derivatives in vivo using Cre-mediated recombination in transgenic mice and demonstrated that a subset of adipocytes originates from the NC during normal development.
The current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of preadipocytes into mature adipocytes. However, the mechanisms that direct MSCs (mesenchymal stem cells) down the adipocyte lineage remain largely unknown. Similarly, although adipocytes are generally described to derive from mesoderm, the study of the developmental origin of MSCs and adipose tissues has been largely disregarded until now. Functional variations do exist between different adipose tissues, which suggest possible differences in their developmental origin and might explain why some depots are more associated than other to metabolic disorders. This review summarizes the surprising findings that have recently emerged from both embryonic stem cells and lineage‐tracing studies in vivo, unravelling an unsuspected developmental origin for MSCs and adipocytes in the neural crest.
BackgroundThe current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. While major progress has been made in defining the molecular networks that control adipocyte terminal differentiation, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown.ResultsHere we performed genome-wide analysis of gene expression during adipogenesis of mouse embryonic stem cells (ESCs). We then pursued comprehensive bioinformatic analyses, including de novo functional annotation and curation of the generated data within the context of biological pathways, to uncover novel biological functions associated with the early steps of adipocyte development. By combining in-depth gene regulation studies and in silico analysis of transcription factor binding site enrichment, we also provide insights into the transcriptional networks that might govern these early steps.ConclusionsThis study supports several biological findings: firstly, adipocyte development in mouse ESCs is coupled to blood vessel morphogenesis and neural development, just as it is during mouse development. Secondly, the early steps of adipocyte formation involve major changes in signaling and transcriptional networks. A large proportion of the transcription factors that we uncovered in mouse ESCs are also expressed in the mouse embryonic mesenchyme and in adipose tissues, demonstrating the power of our approach to probe for genes associated with early developmental processes on a genome-wide scale. Finally, we reveal a plethora of novel candidate genes for adipocyte development and present a unique resource that can be further explored in functional assays.
Key events leading to terminal differentiation of preadipocytes into adipocytes have been identified in recent years. However, signaling pathways involved in the decision of stem cells to follow the adipogenic lineage have not yet been characterized. We have previously shown that differentiating mouse embryonic stem (mES) cells give rise to functional adipocytes upon an early treatment with retinoic acid (RA). The goal of this work was to identify regulators of RA-induced commitment of mES cells to the adipocyte lineage. First, we investigated the role of RA receptor (RAR) isotypes in the induction of mES cell adipogenesis. Using synthetic retinoids selective of RAR isotypes, we show that RARbeta activation is both sufficient and necessary to trigger commitment of mES cells to adipocytes. Then, we performed a small-scale drug screening to find signaling pathways involved in RARbeta-induced mES cell adipogenesis. We show that pharmacological inhibitors of glycogen synthase kinase (GSK) 3, completely inhibit RARbeta-induced adipogenesis in mES cells. This finding uncovers the requirement of active GSK3 in RARbeta-induced commitment of mES cells toward the adipocyte lineage. Finally, we investigated the role of the Wnt pathway, in which GSK3 is a critical negative regulator, in adipocyte commitment by analyzing Wnt pathway activity in RA- and RARbeta-induced mES cell adipogenesis. Our results suggest that although RARbeta and active GSK3 are required for RA-induced adipogenesis, they might be acting through a Wnt pathway-independent mechanism.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.