4. Discussion
4.7 Conclusions
In conclusion, we report a novel function for the AP-1 transcription factor Fra1 in regulating adipocyte differentiation. Fra1 is expressed in adipose tissue and overexpression causes a block in adipocyte differentiation in vitro and in vivo, due to a direct inhibition of C/ebpα expression (Fig. 4.1). Therefore, these findings indicate a diverging role of the different Fos family members during adipocyte differentiation, with in vivo experiments showing that one Fos family member namely ∆FosB, can lead to a lipodystrophic phenotype due to a systemic regulation of metabolism and a second one, Fra1, acting locally and cell-autonomously on the differentiation of adipocytes and osteoblasts.
Figure 4.1: Supposed function of Fra1 on adipocyte differentiation. Mesenchymal progenitor cells have the capacity to differentiate, amongst others, to osteoblasts and adipocytes. Thereby, adipocyte differentiation is regulated by the transcription factors C/ebpβ and δ, that lead to the expression of Pparγ2 and C/ebpα. We suppose Fra1 to regulate adipogenesis by inhibiting the expression C/ebpα.
This work is highly relevant for human health. Indeed, the growing incidence of obesity, leading to an increased susceptibility for type 2 diabetes and cardiovascular diseases, clearly underlines the importance of gaining detailed insight into the mechanistic basis of adipogenesis. In addition, various studies have described the systemic interaction of bone and adipose tissue. However factors locally co-regulating adipocyte and osteoblast differentiation as well as their influence on the glucose and insulin metabolism are still largely unknown. In this thesis we identified Fra1 as being one of these factors.
maturation
mesenchymal progenitor
cell
pre-adipocyte mature
adipocyte determination/
commitment differentiation
immature adipocyte C/ebpββββ
C/ebpδδδδ
Pparγγγγ2
osteoblast C/ebpαααα
Fra-1
Glut4 (insulin-stimulated glucose transport)
CD36 (lipid transport)
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