Modulation of transcriptional activity of nuclear receptors PPAR-gamma, GR and TR-alpha by mTORC1 during and after adipogenesis

Abstract

Understanding the mechanisms involved in adipocyte proliferation and differentiation is essential for the development of therapeutic agents in order to control obesity and related diseases. The proliferation of progenitor cells and their differentiation into mature adipocytes (adipogenesis) are orchestrated by transcription factors and epigenomic events, that modulate the expression of several genes involved in these processes. Although mTOR activation is essential for cellular proliferation and adipogenesis, the interaction of this pathway with nuclear receptors, coregulators and epigenetic modifications driving adipogenesis is still unknown. Therefore, the present proposal aims to investigate the involvement of mTOR complex 1 (mTORC1) in modulating the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPAR-gamma), glucocorticoid receptor (GR) and thyroid hormone receptor alpha (TR-alpha). mTORC1 gain and loss of function experiments will be performed in vitro in adipose-derived stromal vascular precursor cells, 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts (MEF) and in vivo in genetically-modified mice with adipose tissue specific activation of mTOR (adipose tissue-specific TSC knockout) fed with an obesogenic diet. The following parameters will be investigated: gene expression profile, histone modifications and DNA methylation in the promoters of genes responsive to PPAR-gamma, GR and TR-alpha, as well as, DNA methyltransferase and coregulator gene expression and their interaction with PPAR-gamma, GR, TR-alpha. Moreover, metabolic processes related to the uptake and utilization of glucose and lipids in the adipose tissue will also be investigated.