Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Abstract

The formation of adipocytes during embryogenesis has been largely understudied. However, preadipocytes appear to originate from multipotent mesenchymal stromal/stem cells which migrate from the mesoderm to their anatomical localization. Most studies on adipocyte formation (adipogenesis) have used preadipocytes derived from adult stem/stromal cells. Adipogenesis consists of two phases, namely commitment and terminal differentiation. This review discusses the role of signalling pathways, epigenetic modifiers, and transcription factors in preadipocyte commitment and differentiation into mature adipocytes, as well as limitations in our understanding of these processes. To date, a limited number of transcription factors, genes and signalling pathways have been described to regulate preadipocyte commitment. One reason could be that most studies on adipogenesis have used preadipocytes already committed to the adipogenic lineage, which are therefore not suitable for studying preadipocyte commitment. Conversely, over a dozen molecular players including transcription factors, genes, signalling pathways, epigenetic regulators, and microRNAs have been described to be involved in the differentiation of preadipocytes to adipocytes; however, only peroxisome proliferator-activated receptor gamma has proven to be clinically relevant. A detailed understanding of how the molecular players underpinning adipogenesis relate to adipose tissue function could provide new therapeutic approaches for addressing obesity without compromising adipose tissue function.

Keywords: adipocyte commitment; adipocyte progenitor; adipogenesis; adipose tissue; epigenetic regulator; miRNA; signalling pathway; transcription factor.

Figure 1

Molecular regulation of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha (C/EBPα) expression during adipogenesis. Signalling pathways are shaded purple, miRNAs in italics, enzymes in bold, transcription factors in red, epigenetic modifications underlined, protein complexes and genes in standard font and the master regulators of terminal differentiation shaded grey.

Figure 2

Transcriptional regulation of adipogenesis. Transcription factors Zfp423, Zfp467, EBF1 and BCL6 promote preadipocyte commitment into the adipogenic lineage, while RUNX1T1 inhibits this process. Expression of PPARγ and C/EBPα is central to preadipocyte commitment and terminal differentiation, and several other transcription factors are known to regulate PPARγ and C/EBPα expression downstream. Activation of either PPARγ or C/EBPα transactivates the other. Krox20, ZNF638, KLF 4 and 9 activate C/EBPβ expression, which in turn activates PPARγ and thus promotes adipogenesis. SOX9 on the other hand binds to and suppresses C/EBPβ promoter activity and inhibits adipogenesis. KLF 5, 6 and 9, SOX6, EBF1, STAT5, C/EBPδ activate PPARγ expression thereby promoting adipogenesis. GATA2 and KLF2 inhibit PPARγ activation and suppress adipogenesis. STAT3, KLF15, AP-1, LMO3, FOXO1 and ZBTB16 are other transcription factors are reported to promote preadipocyte differentiation, while GATA3, ZFP521, SMAD 2 and 3, KLF 3 and 7 are reported to suppress it.