Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6-Methyladenosine-Mediated Post-Transcriptional Regulation

Abstract

Obesity is a critical risk factor causing the development of metabolic diseases and cancers. Its increasing prevalence worldwide has aroused great concerns of the researchers on adipose development and metabolic function. During adipose expansion, adipogenesis is a way to store lipids as well as to avoid lipotoxicity in other tissues, and may be an approach to offset the negative metabolic effects of obesity. In this Review, the transcriptional regulation of adipogenesis is outlined to characterize numerous biological processes in research on the determination of adipocyte fate and regulation of adipogenic differentiation. Notably, one of the post-transcriptional modifications of mRNA, namely, N⁶-methyladenosine (m⁶A), has been recently found to play a role in adipogenesis. Here, the roles of m⁶A-related enzymes and proteins in adipogenesis, with a particular focus on how these m⁶A-related proteins function at different stages of adipogenesis, are mainly discussed. The Review also highlights the coordination role of the transcriptional and post-transcriptional (RNA m⁶A methylation) regulation in adipogenesis and related biological processes. In this context, a better understanding of adipogenesis at both the transcriptional and post-transcriptional levels may facilitate the development of novel strategies to improve metabolic health in obesity.

Keywords: RNA m6A modification; adipogenesis; obesity; transcription factors.

Figure 1

Overview of adipogenesis. Mesenchymal stem cells are also capable of forming adipocytes, myoblasts, osteoblasts, and chondroblasts. Adipogenesis is the process by which fibroblast‐like progenitor cells restrict their fate to adipogenic lineage (preadipocytes, also called adipogenic progenitor cells or adipogenic stem cells), finally differentiating to form adipocytes. There is now evidence showing that adipocytes can dedifferentiate back to fibroblast‐like progenitor cells in response to metabolic environments. The dedifferentiated cells can proliferate and redifferentiate to become adipocytes.

Figure 2

Regulation of adipogenesis. Adipogenesis is orchestrated by a complex of regulation cascades. When receiving a number of extracellular signals such as Wnts and BMPs, transcription factors, epigenetic and post‐transcriptional regulators are activated, promoting or inhibiting adipogenesis.

Figure 3

Impact of m⁶A on mRNA abundance in adipogenesis. The “writer”‐methyltransferase complexes METTL3, METTL14, and WTAP; “eraser”‐demethylase FTO and ALKBH5; “reader”‐m⁶A binding proteins YTH family and IGF2BPs affect m⁶A methylation and RNA metabolism of key genes (such as Runx1t1) to regulate adipogenesis.

Figure 4

Complex regulation at transcriptional and post‐transcriptional levels by m⁶A modification in adipogenesis. (1) m⁶A‐related proteins regulate the transcription of key regulators to mediate adipogenesis in an m⁶A modification‐dependent manner. (2) m⁶A‐related proteins play a direct role in transcriptional regulation. (3) m⁶A‐related proteins may be transcriptionally regulated. (4) Besides transcriptional regulation, transcription factors interact with m⁶A‐related proteins to regulate m⁶A methylation.

Figure 5

Potential inhibitors of FTO to regulate obesity‐related homeostasis.