Peroxisome Proliferator-Activated Receptor Gamma/Signal Transducers and Activators of Transcription 5A Pathway Plays a Key Factor in Adipogenesis of Human Bone Marrow-Derived Stromal Cells and 3T3-L1 Preadipocytes

Abstract

Adipogenesis is largely dependent on the signal transducers and activators of transcription (STAT) pathway. However, the molecular mechanism of the STAT pathway in the adipogenesis of human bone marrow-derived stromal cells (hBMSCs) remains not well understood. The purpose of this research was to characterize the transcriptional regulation involved in expression of STAT5A and STAT5B during adipogenesis in hBMSCs and 3T3-L1 cells. The expression of STAT5A and STAT5B increases with the onset of adipogenesis in hBMSCs and 3T3-L1 cells. The PPAR response elements regulatory element of STAT5A exists at a promoter region ranging from -346 to -101, and the CCAAT/enhancer-binding protein (C/EBP) regulatory element is located at -196 to -118 of the STAT5B promoter. C/EBPb and C/EBPa bound to the STAT5B promoter region, whereas peroxisome proliferatoractivated receptor g (PPARg) bound to STAT5A. RNA interference of STAT5A completely blocked differentiation, whereas the inhibition of STAT5B only partially blocked differentiation. We propose that C/EBPa, C/EBPb, and PPARg control adipogenesis by regulating STAT5B and STAT5A and that STAT5A is necessary, whereas STAT5B plays a supplementary role during adipogenesis. Further, the regulation of PPARg-STAT5 by C/EBPb signaling seems to be the crucial adipogenesis pathway-initiating cascade of the various adipogenic genes.

In utero growth restriction and catch-up adipogenesis after developmental di (2-ethylhexyl) phthalate exposure cause glucose intolerance in adult male rats following a high-fat dietary challenge

“…Bmp2 and Bmp4 have been shown to drive stem cell commitment, giving rise to preadipocytes [49], and members of the STAT family of proteins have also been implicated in adipogenic commitment [50, 51]. In the current study, males developmentally exposed to DEHP had decreased Bmp2, Bmp4, Stat1 , and Stat5a expression at weaning, which was also associated with a significant decrease in adipocyte density (as a marker of cell number) in adulthood.…”

The role of JAK–STAT signaling in adipose tissue function

“…Interestingly, STAT5B was unable to promote adipogenesis in non-precursor cells, but it did enhance STAT5A-induced fat cell differentiation, indicating distinct roles for STATs 5A and 5B in regulating adipogenesis [27]. RNA interference studies support a supplementary role of STAT5B in fat cell differentiation [38]. Studies using antisense Stat5 oligonucleotides as well as constitutively active and dominant-negative STAT5 constructs have demonstrated that STAT5 proteins mediate the pro-adipogenic activity of growth hormone on preadipocytes [39,79,108].…”

“…Interestingly, cooperative binding of C/EBPβ and STAT5A occurs during a very early stage of adipogenesis and suggests that STAT5A is involved in chromatin remodeling and priming of regulatory sites for subsequent binding by other transcription factors [82]. Intriguingly, in human bone marrow-derived stromal cells induced to undergo adipogenesis, PPARγ also binds to the STAT5A promoter while C/EBPα and C/EBPβ bind the STAT5B promoter region [38]. Thus, there exists a complex interplay of STAT5 proteins with other adipogenic transcriptional regulators to orchestrate the stages of differentiation leading to the biochemical and morphological changes associated with the mature lipid-laden fat cell.…”

Expression and Function of PPARs in Placenta

“…A direct relationship between the PPARs activation and the inhibition of STAT5 mediated transcription has been reported [68, 69]. The PPARs do not block STAT5 tyrosine phosphorylation or do not inhibit DNA-binding activity but inhibit the transcriptional activity of STAT5.…”