The Ubiquitin Ligase Siah2 Regulates PPARγ Activity in Adipocytes

Moderate reductions in peroxisome proliferator-activated receptor (PPAR)gamma levels control insulin sensitivity as effectively as activation of PPAR gamma in adipocytes by the thiazolidinediones. That observation suggests that PPAR gamma activity can be regulated by modulating the amount of PPAR gamma protein in adipocytes. Activation of PPAR gamma in adipocytes is linked to changes in PPAR gamma protein levels via increased degradation of PPAR gamma proteins by the ubiquitin proteasome system. Identification of the ubiquitin ligase or ligases that recognize ligand bound PPAR gamma is an essential step in determining the physiological significance of the relationship between activation and ubiquitin-dependent degradation of PPAR gamma. Using an RNA interference-based screen, we identified five RING (really interesting new gene)-type ubiquitin ligases that alter PPAR gamma protein levels in adipocytes. Here, we demonstrate that Drosophila seven-in-absentia homolog 2 (Siah2), a mammalian homolog of Drosophila seven-in-absentia, regulates PPAR gamma ubiquitylation and ligand-dependent activation of PPAR gamma in adipocytes. We also demonstrate that Siah2 expression is up-regulated during adipogenesis and that PPAR gamma interacts with Siah2 during adipogenesis. In addition, Siah2 is required for adipogenesis. These data suggest that modulation of PPAR gamma protein levels by the ubiquitin ligase Siah2 is essential in determining the physiological effects of PPAR gamma activation in adipocytes. (Endocrinology 153: 1206-1218, 2012)