Forming functional fat: a growing understanding of adipocyte differentiation

Abstract

Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages: commitment of mesenchymal stem cells to a preadipocyte fate and terminal differentiation. Cell shape and extracellular matrix remodelling have recently been found to regulate preadipocyte commitment and competency by modulating WNT and RHO-family GTPase signalling cascades. Adipogenic stimuli induce terminal differentiation in committed preadipocytes through the epigenomic activation of peroxisome proliferator-activated receptor-γ (PPARγ). The coordination of PPARγ with CCAAT/enhancer-binding protein (C/EBP) transcription factors maintains adipocyte gene expression. Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally.

Figure 1:. Cues influencing white adipogenic progression.

Differentiation of multipotent mesenchymal stem cells (MSCs) to mature adipocytes involves a complex integration of cytoarchitecture, signalling pathways, and transcriptional regulators. The first step of adipogenesis is the transition of embryonic stem cells to MSCs (not shown.) MSCs then transition to committed white preadipocytes (mediated by factors such as cell shape, confluency or matrix stiffness). Alternatively, MSCs can be stimulated to differentiate into myoblasts, chondrocytes or osteoblasts. Committed white preadipocytes can become mature white adipocytes upon addition of adipogenic stimuli, such as glucocorticoids, insulin and cyclin AMP. Factors emphasized in this Review are shown along the adipogenic progression at the stage where they act on precursor cells. Factors that have been shown to play a part during different phases of adipogenesis are listed multiple times.

Figure 2:. Relationship between white and brown adipogenesis.

Historically, white and brown adipocytes were thought to derive from the same precursor cell. However, brown adipocytes instead share a common MYF5/PAX7-positive precursor with muscle cells (Box 1). The MYF5/PAX7-positive precursor is driven to brown adipocyte terminal differentiation by PPARγ and C/EBPs cooperating with the transcriptional co-regulator PRDM16. By contrast, PRDM16 does not affect white adipogenesis. White adipocytes can also be stimulated to display characteristics of brown adipocytes by cold exposure, β-adrenergic signalling, and thiazolidinediones, which appear to function via the indicated factors.

Figure 3:. WNT signalling in adipogenesis.

In the presence of canonical WNT ligands, such as WNT10B, β-catenin translocates into the nucleus, where it recruits a co-activator complex to TCF transcription factors and activates WNT target genes. In committed preadipocytes this pathway promotes cell survival, but inhibits adipogenesis. However, the WNT targets that inhibit adipogenesis are not completely understood, it is known that activation of this pathway in MSCs promotes osteogenesis. WNT5B, a non-canonical WNT ligand, promotes adipogenesis by inhibiting β-catenin nuclear localization to these targets. The non-canonical ligand WNT5A also signals to inhibit adipogenesis and promote osteogenesis. This is achieved through the activation of the histone methyltransferase SET domain bifurcated 1 (SETDB1) following the assembly of a SETDB1–NLK–CHD7 complex, inhibiting target gene transcription. It remains unclear which receptors are critical to non-canonical WNT signalling in adipogenesis.

Figure 4:. Rho-GTPase Family in Adipogenesis.

a | RAC-GTP inhibits adipogenesis. Integrins transduce extracellular structural signals into intracellular signalling cascades. Integrin α5, a fibronectin-binding protein, prevents the progression of preadipocytes to mature adipocytes in the absence of adipogenic stimuli by promoting the activation of RAC. Integrin α5 is repressed by adipogenic stimuli, leading to inactivation of RAC and terminal differentiation. b | Regulation of RHO determines MSC lineage fate. The shape of MSCs determines their ability to differentiate into adipocytes or alternate lineages by regulating RHO activity. Factors that favour the inactive form of RHO (RHO-GDP), such as p190-B RHOGAP, promote the adipogenic programme in these precursor cells, by inhibiting ROCK II activation of the actinomyosin cytoskeleton, which leads to the expression of pro-adipogenic WNTs. Conversely, factors that promote Rho-GTP lead to osteogenic or myogenic differentiation programmes, and this is mediated through the expression of anti-adipogenic WNTs and YAP and TAZ. Whether shape directly regulates p190-B RHOGAP or GEFT is unknown. Dashed arrows indicate an indirect interaction.

Figure 5:. Activation of C/EBPs and PPARγ during terminal differentiation.

a | C/EBP activation by adipogenic stimuli. Glucocorticoids and cAMP agonists are common components of the adipogenic stimuli used to promote adipogenesis in both MSCs and committed preadipocytes. Experiments adding these compounds individually have elucidated some of the mechanisms through which C/EBPs, especially C/EBPβ, are induced during adipogenesis. C/EBPβ and C/EBPδ expression is induced upon addition of these adipogenic stimuli. C/EBPβ activity and binding are also regulated independently of its levels by glucocorticoids. In addition, C/EBPβ expression and phosphorylation are regulated by unknown components of the adipogenic cocktail, which may include insulin, growth hormone or BMPs. b | Recruitment of the transcription activation complex to PPARγ. Schematic of the recruitment of transcription factors to the PPARγ locus during adipogenesis. In preadipocytes, PPARγ enhancer regions are occupied by C/EBPβ and C/EBPδ, but are not accessible. Upon addition of adipogenic stimuli, levels of these transcription factors increase and lead to the recruitment of a transcriptional activation complex, including the transcription factors GR, STAT5a and RXR and a co-activator complex. These ‘hotspots’ are also marked by an increase in DNAse I hypersensitivity and activating histone marks. Once PPARγ is robustly activated in differentiation, it can auto-regulate its expression in cooperation with C/EBPα and C/EBPβ.