Adipogenesis at a glance

Abstract

The formation of adipocytes from precursor stem cells involves a complex and highly orchestrated programme of gene expression. Our understanding of the basic network of transcription factors that regulates adipogenesis has remained remarkably unchanged in recent years. However, this continues to be refined with new factors and cofactors becoming superimposed onto the network (White and Stephens, 2010). At the same time attention has also shifted to many other aspects of adipocyte development, including efforts to identify, isolate and manipulate relevant precursor stem cells. Recent studies have revealed new intracellular pathways, processes and secreted factors that can influence the decision of these cells to become adipocytes.Understanding the intricacies of adipogenesis is of major relevance to human disease, as adipocyte dysfunction makes an important contribution to metabolic disease in obesity (Unger et al., 2010). Thus, improving adipocyte function and the complementation or replacement of poorly functioning adipocytes could be beneficial in common metabolic disease. Approximately 10% of adipocytes turn over in human adipose tissue each year, which indicates that ensuring the newly forming adipocytes are appropriately metabolically flexible could substantially improve metabolic diseases (Spalding et al., 2008).This Cell Science at a Glance article reviews the transition of precursor stem cells into mature lipid-laden adipocytes, and the numerous molecules, pathways and signals required to accomplish this.Pluripotent mesenchymal stem cells (MSCs) can be isolated from several tissues, including adipose tissue. Adipose-derived MSCs have the capacity to differentiate into a variety of cell types, including adipocytes, osteoblasts, chondrocytes and myocytes. Until recently, stem cells in the adipose tissue stromal vascular fraction (SVF) have been typically isolated in pools that contain a mixture of cell types, and the ability of these SVF pools to develop into mature adipose depots in vitro or in vivo has been variable (Rodeheffer et al., 2008).More recently, cell surface markers have been identified that define a subpopulation of stromal cells that differentiates into adipocytes and forms functional adipose depots in vivo much more efficiently (Lin−, Sca1+, CD34+, CD24+, a7−, PDGFRα+) (Joe et al., 2010; Rodeheffer et al., 2008; Tang et al., 2008). However, these cells show limited adipogenic capacity in vivo unless host animals are in states conducive to adipose tissue expansion, as occurs during high-fat feeding or in lipodystrophy, which demonstrates the importance of the cellular microenvironment. In addition, differences exist between adipocyte precursors from different fat depots, and this might underlie some of the differences in the expansion of these depots in response to nutrient excess (Joe et al., 2009).Another key advance in this area has been the demonstration that brown and white adipocytes do not develop from common precursors, as previously thought. Rather, the development of thermogenic brown adipocytes is driven by the transcription factor PR-domain-containing 16 (PRDM16) from precursors that can also form myocytes (Kajimura et al., 2009; Seale et al., 2008).Multiple signals can influence whether stem cells form adipocytes, including extracellular factors such as the bone morphogenetic proteins (BMPs) (Huang et al., 2009), transforming growth factor β (TGFβ) (Zamani and Brown, 2010), insulin-like growth factor 1 (IGF1) (Kawai and Rosen, 2010a), interleukin 17 (IL17) (Zúñiga et al., 2010), fibroblast growth factor 1 (FGF1) (Widberg et al., 2009), FGF2 (Xiao et al., 2010) and activin (Zaragosi et al., 2010).Extensive literature demonstrates the importance of WNT signalling in adipocyte development, both in vitro and in vivo, and that suppression of this pathway is essential for adipogenesis to proceed (Christodoulides et al., 2009; Prestwich and MacDougald, 2007). Similarly, the hedgehog (HH) signalling pathway inhibits adipogenesis, although the mechanisms involved are less clear (Cousin et al., 2007; Pospisilik et al., 2010). One study suggests that the receptors that initiate the WNT and HH signalling cascades reside on primary cilia transiently present on differentiating adipocytes (Marion et al., 2009). Impaired cilia formation during adipogenesis results in increased expression of the transcription factor peroxisomal proliferator-activated receptor γ (PPARγ), which suggests that increased adipogenesis might contribute to the obese phenotype of individuals with the inherited ciliopathy Bardet–Biedl syndrome (Marion et al., 2009).Additional intracellular signalling pathways continue to be implicated in adipogenesis and the involvement of known regulators is constantly refined. These pathways and regulators include glutathione (Vigilanza et al., 2010), the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway (Zhang et al., 2011), SMAD signalling (March