PPAR gamma repression mechanism as a target to combat diabetes and obesity

Abstract

Obesity and type 2 diabetes are chronic diseases characterized by increased body fat and insulin resistance. The growing number of new cases per year have been considered alarming and, for this reason, the development of new therapies has considerable importance. In this scenario, nuclear receptors play fundamental roles, being important modulation targets. The PPAR³ is one of these targets, acting effectively in adipogenesis and insulin sensitization. Diverse studies point that repression of PPAR³ or the modulation of its phosphorylation might result in decreasing of its deleterious effects, providing new strategies for insulin sensitization control. Regarding this, in this project, we intend to uncover the main repression mechanisms of PPAR³, relating the events of corepressors recruitment and PPAR³ Ser273 phosphorylation, with the modulation of adipogenesis and insulin resistance. Through structural biology tools (X-ray crystallography, NMR, SAXS), molecular biology assays (cell transactivation, two-hybrid, reporter gene, qPCR), biophysical techniques (microscale thermophoresis, fluorescence anisotropy, FRET) and quantitative characterization of PPAR³/CoR interaction in cells, we will provide better knowledge of the mechanistic aspects of relevant interaction interfaces of PPAR³, which are related to metabolic diseases. The set of obtained results will be extremely important to provide relevant information on the mechanism of action of this receptor, and to generate new targets for drug development targeting the PPAR³ repression, without producing undesirable side effects. (AU)