Dissection of PPAR gama modulation mechanisms as target to treat diabetes and obesity development

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 modulation of PPAR³ through post-translational modifications might result in decreasing in its deleterious effects, providing new strategies for insulin sensitization and obesity control. Regarding this, in this project, we intend to uncover the main PPAR³ modulation mechanisms, relating the events of corepressors recruitment and PPAR³ Ser273 phosphorylation or K268 and K293 deacetylation, with the modulation of adipogenesis and insulin resistance. Through structural biology tools (X-ray crystallography, NMR, SAXS), molecular biology assays (cell transactivation, adipogenesis, browning, two-hybrid, reporter gene, qPCR), molecular biology (qPCR and RNAseq) and biophysical techniques (microscale thermophoresis, fluorescence anisotropy), we will provide better knowledge of the mechanistic aspects of relevant interaction interfaces of PPAR³, which are related to metabolic diseases. In addition, we intend to elucidate mechanism in which PPAR³ regulates adipogenesis and browning, together with UCP-1 and Sirt-1, through the development of organoid models that mimic adipose tissue. 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, without producing undesirable side effects. (AU)