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mTOR complex 1 involvement in the control of macrophage function in the chronic inflammatory response associated with obesity and insulin resistance

Grant number: 11/10783-7
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2011
Effective date (End): November 30, 2015
Field of knowledge:Biological Sciences - Physiology - General Physiology
Principal Investigator:William Tadeu Lara Festuccia
Grantee:Vivian Almeida Paschoal
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):14/04215-4 - Involvement of the transcriptional corepressor NCoR in the development of high fat diet induced hepatic inflammation and insulin resistance, BE.EP.DR


Chronic low-grade inflammation and activation of the nutrient sensitive intracellular mTOR signaling pathway are majorly involved in the development of obesity and associated insulin resistance. The interrelationships between mTOR and inflammation on obesity conditions, however, have not been investigated. Thus, the main goal of this research proposal is to investigate the involvement of mTOR complex 1 in the control of macrophage function and its involvement in the genesis and maintenance of chronic low-grade inflammation associated with obesity. For this, in vivo experiments with loss of function of the mTOR complex 1 (pharmacological inhibition with rapamycin) will be induced in mice made obese by a high fat diet where we will evaluate: 1) glucose and insulin tolerance; 2) insulin and toll-like receptor intracellular signaling in macrophages and adipocytes; 3) plasma levels of cytokines and metabolites; 4) adipose tissue cellular composition; 5) macrophage recruitment and activation in adipose tissue; 6) macrophages transition from quiescent M2 to the proinflammatory M1 state; 7) macrophage basal and stimulated cytokine secretion; 8) macrophage triacylglycerol synthesis and activity of lipogenic enzymes; and 9) macrophage and adipocyte gene expression profile regarding transcription factors and related co-activators of cytokine production and lipid synthesis. Items 2, 7, 8 and 9 will be also investigated in vitro in RAW 264.7 cells (immortalized macrophage cell lineage) and primary macrophages derived from bone marrow or peritoneum upon mTOR complex 1 genetic and pharmacologic activation and/or inhibition.

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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)
PASCHOAL, VIVIAN A.; BELCHIOR, THIAGO; AMANO, MARIANE T.; BURGOS-SILVA, MARINA; PEIXOTO, ALBERT S.; MAGDALON, JULIANA; VIEIRA, THAYNA S.; ANDRADE, MAYNARA L.; MORENO, MAYARA F.; CHIMIN, PATRICIA; et al. Constitutive Activation of the Nutrient Sensor mTORC1 in Myeloid Cells Induced by Tsc1 Deletion Protects Mice from Diet-Induced Obesity. MOLECULAR NUTRITION & FOOD RESEARCH, v. 62, n. 17, . (15/19530-5, 12/02270-2, 11/10783-7, 09/15354-7)
PASCHOAL, VIVIAN A.; AMANO, MARIANE T.; BELCHIOR, THIAGO; MAGDALON, JULIANA; CHIMIN, PATRICIA; ANDRADE, MAYNARA L.; ORTIZ-SILVA, MILENE; CASTRO, ERIQUE; YAMASHITA, ALEX S.; ROSA NETO, JOSE CESAR; et al. mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function. Immunobiology, v. 222, n. 2, p. 261-271, . (15/19530-5, 12/02270-2, 11/10783-7, 09/15354-7)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
PASCHOAL, Vivian Almeida. mTOR complex 1 attenuates the proinflammatory macrophage response, and adipose tissue inflammation associated with obesity.. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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