Atypical transcriptional regulators and cofactors of PPARγ

Abstract

Regulation of peroxisome proliferator-activated receptor gamma (PPARg) activity is the result of several events. The first control level is the regulation of the expression of PPARg. Examples of this regulation, during adipogenesis, is the transactivation of the PPARg promoter by transcription factors of the classical pathway, such as C/EBPs or ADD1/SREBP1, but also newly identified factors, such as E2Fs. When preadipocytes re-enter the cell cycle, PPARg expression is induced coincident with an increase in DNA synthesis, suggesting the involvement of the E2F family of cell cycle regulators. E2F1 induces PPARg transcription during clonal expansion, whereas E2F4 represses PPARg expression during terminal adipocyte differentiation. Hence, E2Fs represent the link between proliferative signaling pathways, triggering clonal expansion, and terminal adipocyte differentiation through regulation of PPARg expression. A second regulatory level of PPARg action is interaction with cofactors. We will focus our attention on the atypical PPARg modulators. We have described an interaction between PPARg and the retinoblastoma protein, RB, which is both dependent upon ligand binding by PPARg and upon the phosphorylation status of RB. The interaction between PPARg and RB decreases the transcriptional activity of PPARg through recruitment of the histone deacetylase HDAC3. Inhibition of HDAC activity consequently results in a strong activation of PPARg.

Chemerin, a Novel Peroxisome Proliferator-activated Receptor γ (PPARγ) Target Gene That Promotes Mesenchymal Stem Cell Adipogenesis

“…sion alone caused a mild but significant suppression of cell proliferation during clonal expansion, a finding consistent with that from other models (41). This generalized role for PPAR␥ to inhibit clonal expansion as cells become terminally differentiated is well established (41)(42)(43)(44)(45)(46) and may have also contributed to the failure to achieve a full rescue of adipogenesis in the face of chemerin or CMKLR1 knockdown.…”

“…It is well established that adipogenic clonal expansion is regulated by a variety of cell cycle proteins (42,45,(47)(48)(49)(50)(51)(52)(53). Consistent with a role for chemerin/CMKLR1 signaling in driving the proliferative phase of adipogenic clonal expansion in BMSCs, there was a marked loss of cyclin A2/B2 mRNA and protein expression with chemerin or CMKLR1 knockdown.…”

Transcriptional activation of pref-1 by E2F1 in 3T3 L1 cells

“…Consistent with our results, the phosphorylation of Rb during clonal expansion causes the release of Rb-associated E2F1, which forms the E2F1/DP complex and stimulates the transcriptional activity of PPARγ (10,13). In addition, E2F1 inhibits the expression of the PAI-1 gene, a member of the serine proteinase inhibitor family, resulting in the induction of PPARγ, C/EBPα and AP2 (14).…”

Inhibition of p38MAPK Increases Adipogenesis From Embryonic to Adult Stages

“…However, PGC-1 is not implicated in white adipocyte differentiation (39,40). Although we do not know whether they are phosphorylated by p38MAPK, other PPAR␥ coactivators, such as steroid receptor coactivator, CREB-binding protein, or p300, involved in adipogenesis, represent interesting potential targets (41). Alternatively, PPAR␥ corepressors could also be involved in p38MAPK regulation, especially because they regulate the PPAR␥ transcriptional activity in adipocytes (42).…”