Modulation of the adipogenic master regulator PPARγ

摘要: Obesity is regarded as a major public health problem by the World Health Organization. characterized an increase in adipose tissue, both through amount of fat stored per adipocyte, and generation new adipocytes differentiation pre-adipocyte (adipogenesis), process which transcription factor PPARγ plays significant role. In this thesis we described different aspects PPARγ, tissue adipogenesis. necessary for adipogenesis, maintenance able to regulate many “adipocyte genes” that are lipid glucose metabolism. Many under intense study, here focused on modulation expression activity factor. It known subject post-translational modifications (PTM) such phosphorylation, ubiquitination, acetylation sumoylation. All these marks have effect PPARγ. However, not much was about opposite process: de-modification. We identified PPM1B be phosphatase capable directly binding dephosphorylating serine residue at position 112. general, S112 phosphorylation lowers activity, subsequently leading decreased target gene expression. Knocking down indicated indeed case subset genes. This led conclusion (de)phosphorylation had subtle effects could seen terms specific expression, but adipogenesis whole. Interestingly, second site recently no link has been made between S273 PPM1B. Adipogenesis occurs least two waves; genes C/EBPβ, C/EBPδ, KLF5, CREB, SREBP-1c Krox20 come up early ultimately lead C/EBPα, can than direct role investigated other proteins would regulating PPARG thus Consequently developed siRNA based knockdown screen found Baf57, subunit SWI/SNF chromatin remodeling complex, Phf12 “chromatin-associated” mainly implicated transcriptional repression, Knockdown Baf57/Phf12 impairs adipogenesis; transcriptome analysis reveals inhibited large extent same knockdown. The affected so-called late adipocyte genes, rather mentioned above. Further binds promotor induce its human murine cell lines. Finally discuss potential clinical intervention. Modulation may used order ameliorate obesity if done properly. Full agonists severe side humans, post translational or associated provide alternative answer treatment