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

Grant number: 11/03972-8
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2011
Effective date (End): September 30, 2016
Field of knowledge:Biological Sciences - Physiology - General Physiology
Principal Investigator:William Tadeu Lara Festuccia
Grantee:Juliana Magdalon
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:09/15354-7 - Role of adipose tissue in the development of obesity and associated co-morbidities: investigation of molecular mechanism and search for alternative therapies, AP.JP
Associated scholarship(s):12/20638-7 - Analysis of changes in mRNA translation during adipogenesis and its regulation by mTORC1, BE.EP.DR


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.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MAGDALON, JULIANA; CHIMIN, PATRICIA; BELCHIOR, THIAGO; NEVES, RODRIGO X.; VIEIRA-LARA, MARCEL A.; ANDRADE, MAYNARA L.; FARIAS, TALITA S.; BOLSONI-LOPES, ANDRESSA; PASCHOAL, VIVIAN A.; YAMASHITA, ALEX S.; et al. Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1861, n. 5, p. 430-438, . (10/51906-1, 11/03972-8, 12/25317-4, 15/19530-5, 13/14203-0, 09/15354-7)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
MAGDALON, Juliana. Constitutive adipocyte mTORC1 activation enhances mitochondrial oxidative capacity and reduces visceral adiposity in mice.. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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