PPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wildtype phosphorylated with mutant non-phosphorylated PPAR gamma may have important consequences for the cellular molecular network, the state of which can be shifted from the healthy to a stable diseased state. We found that a group of differentially expressed genes are involved in bi-stable switches and form a core network, the state of which changes with disease progression. These findings support the idea that bi-stable switches may be a mechanism for locking the core gene network into a diseased state and for efficiently propagating perturbations to more distant regions of the network. A structural analysis of the PPAR gamma-RXR alpha dimer complex supports the hypothesis of a major structural change between the two states, and this may represent an important mechanism leading to the differential expression observed in the core network. Cell Death and Disease (2011) 2, e192; doi: 10.1038/cddis.2011.74; published online 11 August 2011