Study of the PPARy-coregulators interactions and its relationship with adipogenesis and insulin resistance

Abstract

Nuclear receptors are regulators of various processes of animal metabolism and therefore play an important role in acting as drugs for various metabolic diseases. The peroxisome proliferator-activated receptor gamma (PPAR³) is the master regulator of general lipid metabolism and insulin sensitivity, being the main responsible for the process of adipogenesis. Its activation occurs through the binding of small molecules to its binding site to ligands (LBD), which induces a conformational change that leads to the recruitment of coactivating proteins, culminating in the transcription of target genes. The enzyme CDK5, highly expressed in obesity frames, acts on PPAR³ by performing phosphorylation in Ser273 located within its LBD, which leads to deregulation of target genes related to insulin resistance. In the presence of PPAR³ agonists, this phosphorylation is blocked, leading to normalization in the expression of the previously deregulated genes. Such inhibition is associated with the antidiabetic effects of PPAR³ agonists used as drugs for treatment against insulin resistance, such as Rosiglitazone. These findings suggest that such phosphorylation may be involved in the pathogenesis of insulin resistance and indicate a new path in the search for drugs for the treatment of insulin resistance. Knowing that Ser273 phosphorylation alters the expression profile of PPAR³ regulated genes without altering its occupancy in the regulatory region of genes, it is evident that the coregulators seem to have a substantial importance in this change. In this project, we propose interaction studies between coregulators and the PPAR³ in order to elucidate the mechanisms that lead to insulin resistance and Type 2 Diabetes. (AU)