Construction of a microphysiological model of steatotic 3D liver culture induced by 3D cultures of obese adipose tissue and modulation of PPAR³-related pathways

Abstract

Obesity, type 2 diabetes, and fatty liver disease are chronic diseases characterized by increased body fat, inflammation, and insulin resistance. Its increasing numbers of new cases are considered alarming and therefore the development of new therapies is of great importance. In this context, PPAR³ is a modulation target, acting effectively in adipogenesis and insulin sensitization. Several studies indicate that the modulation of its post-translational modifications would result in the reduction of its deleterious effects, providing new strategies to control insulin sensitization and obesity. Other studies indicate that the indirect modulation of the pathways controlled by this receptor, for example, via SIRT-1 activation or by the presence of GDF15, could be an interesting strategy for the development of new therapies. In this project we will develop a microphysiological model of 3D cultures of white adipose tissue and liver to study obesity and steatosis, and the models will be integrated into microfluidic systems and will be converted into obese adipose tissue and steatotic liver. In parallel, we will finalize our studies on the influence of PPAR phosphorylation and deacetylation by CDK5 and SIRT1. In this sense, we will finalize the studies of molecular and structural details of PPAR³-co-regulators, CDK5 and SIRT1 interactions and we intend to unveil new PPAR³ modulation mechanisms with direct influence on adipogenesis, browning and insulin sensitization processes. Finally, we will evaluate the direct and indirect modulation of the PPAR³ receptor in the microphysiological model developed, in the case of direct modulation, we will use selective ligands that inhibit the phosphorylation of the receptor, in the case of indirect modulation, we will seek modulation through the activation of SIRT1 and presence of GDF15. Through these objectives, we intend to expand the knowledge about the molecular and physiological bases of obesity, in addition to proposing robust models of phenotypic assays that can reduce the demand for animal models, and to relate possible modulations of PPAR³ to the development of obesity. (AU)