Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) 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 wild-type phosphorylated with mutant non-phosphorylated PPARγ 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 PPARγ–RXRα 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.
Highlights
Proteins exist as populations of states of different structures and energies, including native structural states, malfunctioning and highly unfolded species
Protein population shift as a result of external stimuli can be observed in the post-translational modifications of crystallin protein leading to cataract formation[7] or the misfolding of S100 proteins caused by changing metal ion concentrations, which are implicated in cancer, neurodegenerative, inflammatory and autoimmune diseases.[8]
The genes with the highest betweenness centrality were HIF1A, early growth response 1 (EGR1), STAT1 and CXCL12 (chemokine (C–X–C motif) ligand 12) and they are all overexpressed in the case of phosphorylated Peroxisome proliferator-activated receptor gamma (PPARg). We examined these genes in more detail with regard to their association with adipogenesis, for which PPARg is the master regulator under any condition, to confirm that our core network is consistent with experimental studies. We found that this was the case: the role of the transcription factor HIF1A in adipocyte differentiation has been described previously,[23] EGR1 functions as a transcriptional regulator the expression of which is rapidly induced during the differentiation of murine 3T3-L1 adipocytes,[24] STAT1 acts as a transcription activator, which is rapidly activated in the 3T3-L1 adipocyte cell culture model,[25] and CXCL12 is a chemokine, which demonstrates a significant increase in expression in differentiating 3T3-L1 preadipocytes.[26]
Summary
Proteins exist as populations of states of different structures and energies, including native structural states, malfunctioning and highly unfolded species. Biological function might be altered by protein misfolding, impairment of protein-binding events and malfunctioning of the allosteric control mechanism As transition between these states often requires crossing high-energy barriers, penetration of the full energy landscape under unperturbed conditions is low. The metabolic syndrome describes a cluster of metabolic abnormalities encompassing elevated fasting glucose concentrations, increased waist circumference, increased triglycerides, low HDL cholesterol levels and high blood pressure.[9]. It occurs with a prevalence of 20–25% worldwide according to the IDF (International Diabetes Federation),[10,11] and is on the rise, especially in the elderly population, and more alarming even in children and adolescents.[12]. Total and cardiovascular mortality is increased in the metabolic syndrome, and the risk of developing overt type II diabetes is increased fivefold.[13,14] From a pathophysiological point of view, the metabolic syndrome is widely held to be caused by central adiposity that can lead to insulin resistance under given genetic and environmental circumstances.[15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
