Cell Science at a Glance 2681 Adipogenesis at a Stephens, 2010). At the same time attention has This Cell Science at a Glance article reviews also shifted to many other aspects of adipocyte the transition of precursor stem cells into mature glance development, including efforts to identify, lipid-laden adipocytes, and the numerous isolate and manipulate relevant precursor stem molecules, pathways and signals required to Christopher E. Lowe, Stephen cells. Recent studies have revealed new accomplish this. O’Rahilly and Justin J. Rochford* intracellular pathways, processes and secreted University of Cambridge Metabolic Research factors that can influence the decision of these Adipocyte stem cells Laboratories, Institute of Metabolic Science, cells to become adipocytes. Pluripotent mesenchymal stem cells (MSCs) Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK Understanding the intricacies of adipogenesis can be isolated from several tissues, including *Author for correspondence ([email protected]) is of major relevance to human disease, as adipose tissue. Adipose-derived MSCs have the Journal of Cell Science 124, 2681-2686 adipocyte dysfunction makes an important capacity to differentiate into a variety of cell © 2011. Published by The Company of Biologists Ltd doi:10.1242/jcs.079699 contribution to metabolic disease in obesity types, including adipocytes, osteoblasts, (Unger et al., 2010). Thus, improving adipocyte chondrocytes and myocytes. Until recently, The formation of adipocytes from precursor function and the complementation or stem cells in the adipose tissue stromal vascular stem cells involves a complex and highly replacement of poorly functioning adipocytes fraction (SVF) have been typically isolated in orchestrated programme of gene expression. could be beneficial in common metabolic pools that contain a mixture of cell types, and the Our understanding of the basic network of disease. Approximately 10% of adipocytes turn ability of these SVF pools to develop into transcription factors that regulates adipogenesis over in human adipose tissue each year, which mature adipose depots in vitro or in vivo has has remained remarkably unchanged in recent indicates that ensuring the newly forming been variable (Rodeheffer et al., 2008). years. However, this continues to be refined adipocytes are appropriately metabolically More recently, cell surface markers have been with new factors and cofactors becoming flexible could substantially improve metabolic identified that define a subpopulation of stromal superimposed onto the network (White and diseases (Spalding et al., 2008). cells that differentiates into adipocytes and Journal of Cell Science (See poster insert) 2682 Journal of Cell Science 124 (16) forms functional adipose depots in vivo much regulators include glutathione (Vigilanza et al., proteins (C/EBPs) C/EBP and C/EBPd. These more efficiently (Lin–, Sca1+, CD34+, CD24+, 2010), the Janus kinase-signal transducer and are key early regulators of adipogenesis, and the a7–, PDGFR+) (Joe et al., 2010; Rodeheffer et activator of transcription 3 (JAK-STAT3) anti-adipogenic preadipocyte factor 1 (PREF1) al., 2008; Tang et al., 2008). However, these pathway (Zhang et al., 2011), SMAD signalling has recently been shown to act through SOX9 in cells show limited adipogenic capacity in vivo (Marchildon et al., 2010; Tan et al., 2011), the direct regulation of the promoters for the unless host animals are in states conducive to ribosomal protein S6 kinase 1 (S6K1) genes encoding C/EBP and C/EBPd (Wang adipose tissue expansion, as occurs during high- (Carnevalli et al., 2010) and components of the and Sul, 2009). In addition, C/EBP appears to fat feeding or in lipodystrophy, which insulin signalling cascade, such as AKT (Zhang, be the target of the proadipogenic demonstrates the importance of the cellular H. H. et al., 2009) and a newly discovered desumoylating enzyme sentrin-specific microenvironment. In addition, differences exist regulator of this pathway, inositol peptidase 2 (SENP2) (Chung et al., 2010). between adipocyte precursors from different fat pyrophosphate (Chakraborty et al., 2010). New SENP2 is required to reduce the levels of depots, and this might underlie some of the transcriptional regulators of stem cell fate that C/EBP sumoylation, which would otherwise differences in the expansion of these depots in are controlled by these pathways also continue lead to its increased ubiquitylation and response to nutrient excess (Joe et al., 2009). to be identified. These include retinoblastoma degradation of the protein. Another key advance in this area has been the protein (RB) (Calo et al., 2010), p53 Among the targets of C/EBP and C/EBPd demonstration that brown and white adipocytes (Molchadsky et al., 2008), the proto- are the promoters of the genes encoding the key do not develop from common precursors, as oncoprotein MAF (Nishikawa et al., 2010), adipogenic transcription factors C/EBP and previously thought. Rather, the development of zinc-finger protein 423 (ZFP423) (Gupta et al., PPARg and the regulator of lipogenic genes thermogenic brown adipocytes is driven by the 2010) and SOX9 [for SRY (sex-determining SREBP1 (for sterol-regulatory-element-binding transcription factor PR-domain-containing 16 region Y)-box 9] (Wang and Sul, 2009). protein 1) (Payne et al., 2010; Rosen and (PRDM16) from precursors that can also form In addition to external signals, cell shape also MacDougald, 2006; White and Stephens, 2010). myocytes (Kajimura et al., 2009; Seale et al., influences the process of adipogenesis. Whereas PPARg activates the promoter of the gene 2008). rounded MSCs are more likely to become encoding C/EBP and vice versa, creating a adipocytes, widely spread cells favour positive-feedback loop. In addition, PPARg and Signals to differentiate osteogenesis (Feng et al., 2010; Kilian et al., C/EBP induce the expression of genes that are Multiple signals can influence whether stem cells 2010). Related to this, extracellular remodelling involved in insulin sensitivity, lipogenesis and form adipocytes, including extracellular factors has been shown to have important roles in lipolysis, including those encoding glucose such as the bone morphogenetic proteins (BMPs) adipocyte and adipose tissue development transporter GLUT4 (also known as SLC2A4), (Huang et al., 2009), transforming growth factor (Divoux and Clement, 2011; Mariman and fatty-acid-binding protein (FABP4, also known (TGF) (Zamani and Brown, 2010), insulin- Wang, 2010). For example, loss of the as adipocyte protein 2, aP2), lipoprotein lipase like growth factor 1 (IGF1) (Kawai and Rosen, membrane-bound matrix metalloproteinase (LPL), sn-1-acylglycerol-3-phosphate acyl- 2010a), interleukin 17 (IL17) (Zúñiga et al., MMP14 impairs adipogenesis in vivo (Chun et transferase 2 (AGPAT2), perilipin and the 2010), fibroblast growth factor 1 (FGF1) al., 2006). Importantly, this defect was only secreted factors adiponectin and leptin. Recent (Widberg et al., 2009), FGF2 (Xiao et al., 2010) apparent in a three-dimensional, but not a two- genome-wide binding analyses have revealed Journal of Cell Science and activin (Zaragosi et al., 2010). dimensional, cell culture system. This highlights that PPARg and C/EBP cooperate on multiple Extensive literature demonstrates the the limitations of the two-dimensional cell binding sites in promoter regions, together importance of WNT signalling in adipocyte culture models of adipogenesis, which regulating a wide range of genes expressed in development, both in vitro and in vivo, and that recapitulate many intracellular signals and tran- developing and mature adipocytes (Lefterova et suppression of this pathway is essential for scriptional regulators of adipogenesis but not al., 2008; Nielsen et al., 2008). An array of adipogenesis to proceed (Christodoulides et al., other aspects of adipocyte development that are factors regulates this central transcriptional 2009; Prestwich and MacDougald, 2007). important in vivo. Similarly angiogenesis network, such as STAT5, C/EBP homologous Similarly, the hedgehog (HH) signalling influences adipogenesis and adiposity, but these protein 10 (CHOP10, also known as DNA- pathway inhibits adipogenesis, although the effects can only be fully appreciated from in damage-inducible transcript 3, DDIT3) and mechanisms involved are less clear (Cousin et vivo studies (Christiaens and Lijnen, 2010). members of the Krüppel-like factor (KLF) al., 2007; Pospisilik et al., 2010). One study family (Rosen and MacDougald, 2006; White suggests that the receptors that initiate the WNT Regulating gene expression during and Stephens, 2010). Positive regulators include and HH signalling cascades reside on primary adipogenesis early growth response-2 (EGR2, also known as cilia transiently present on differentiating The transcriptional cascade regulating the KROX20) (Chen et al., 2005), early B cell adipocytes (Marion et al., 2009). Impaired cilia terminal differentiation of adipocytes has been factor-1 (EBF1, also known as COE1) (Jimenez formation during adipogenesis results in reviewed in detail elsewhere (Farmer, 2006; et al., 2007), KLF4 (Birsoy et al., 2008) and increased expression of the transcription factor Rosen and MacDougald, 2006; Tontonoz and brain and muscle Arnt-like protein 1 (BMAL1, peroxisomal proliferator-activated receptor g Spiegelman, 2008). The following sections will also known as ARNTL1) (Shimba et al., 2005), (PPARg), which suggests that increased place newly discovered regulators in the context whereas