Transcriptional control of adipocyte formation

Abstract

A detailed understanding of the processes governing adipose tissue formation will be instrumental in combating the obesity epidemic. Much progress has been made in the last two decades in defining transcriptional events controlling the differentiation of mesenchymal stem cells into adipocytes. A complex network of transcription factors and cell-cycle regulators, in concert with specific transcriptional coactivators and corepressors, respond to extracellular stimuli to activate or repress adipocyte differentiation. This review summarizes advances in this field, which constitute a framework for potential antiobesity strategies.

Figure 1. Induction of adipogenesis by a cascade of transcription factors

Exposure of preadipocytes to a cocktail of adipogenic inducers comprised of insulin, glucocorticoids, agents that elevate cAMP (isobutylmethylxanthine), and fetal bovine serum activates expression of several transcription factors that converge on PPARγ. PPARγ then induces C/EBPα expression, and together, these factors oversee terminal adipogenesis.

Figure 2. Role of cell-cycle proteins in regulating adipogenesis

An alternative pathway to that presented in Figure 1 exists whereby E2Fs and associated pocket proteins regulate expression of PPARγ1. Activation of PPARγ2 likely occurs through the induction of C/EBPα by PPARγ1, and C/EBPα then induces PPARγ2 expression. This model is consistent with a role for clonal expansion in promoting adipogenesis. G₀, G₁, and S correspond to phases of the cell cycle, while G_D is a term used to define the growth-arrested state of terminally differentiated cells.

Figure 3. Negative control of adipogenesis

Negative regulators inhibit expression of PPARγ and C/EBPα by attenuating the activity of components of the cascade presented in Figure 1. Several of these negative factors appear to converge on C/EBPβ, supporting its role as a principal regulator of adipogenesis.

Figure 4. Coregulators and adipogenesis

The activity of the adipogenic transcription factors is regulated by association with various corepressors (red boxes) or coactivators (green boxes) at different stages of differentiation of both brown as well as white preadipocytes. The Mediator shown to be associating with PPARγ corresponds to the TRAP (thyroid hormone receptor-associated protein) transcriptional coactivator complex, which interacts physically with PPARγ through the TRAP220 subunit. See text for detailed discussion of the participation of the various protein complexes in controlling each of the transcription factors.