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Involvement of mTOR complex 1 and 2 in secretory control of lipid and protein inflammatory mediators by adipocytes in obesity and insulin resistance conditions.

Grant number: 12/25317-4
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): September 01, 2013
Effective date (End): November 30, 2015
Field of knowledge:Biological Sciences - Physiology - General Physiology
Principal Investigator:William Tadeu Lara Festuccia
Grantee:Patricia Chimin
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


Obesity is a multifactorial disease characterized by a low-grade inflammation in which white adipose tissue plays a very important role producing and secreting anti and pro-inflammatory adipokines and lipid mediators derived from arachidonic (eicosanoids), eicosapentaenoic and docosahexaenoic fatty acids. Several pieces of evidence indicate that in obesity and insulin resistance there is an imbalance in the production of these mediators favoring a pro-inflammatory adipose tissue profile. Besides the importance of these lipid mediators along with adipokines in the control of adipose tissue inflammation, little information is known about the regulation of the production and secretion of these molecules by adipocytes in normal conditions and in obesity and insulin resistance. Furthermore, the effects of these inflammatory mediators on the recruitment, metabolism and phenotype of macrophages resident in adipose tissue and adipocyte metabolism also need to be investigated. Therefore the main goal of this proposal is to investigate the mechanisms involved in the control of the production and secretion of adipokines and inflammatory lipid mediators by adipocytes at normal conditions and in obesity associated insulin resistance with a special emphasis in the elucidation of the involvement of mTOR complexes 1 and 2 in these processes. It will also be investigated the effect of these inflammatory lipid mediators in the recruitment, metabolism and phenotype of macrophages residing in adipose tissue and on adipocyte metabolism. To accomplish these goals we will carry out in vivo and in vitro experiments with mice and adipocytes with genetic or pharmacological inhibition of mTOR complex 1 or 2. Preliminary results obtained in adipocytes (3T3-L1) indicate an important participation of mTOR complexes 1 and 2 in the alterations gene expression profile of cyclooxygenases 1 and 2 and other adipokines induced by LPS.

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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)
CASTRO, ERIQUE; VIEIRA, THAYNA S.; OLIVEIRA, TIAGO E.; ORTIZ-SILVA, MILENE; ANDRADE, MAYNARA L.; TOMAZELLI, CAROLINE A.; PEIXOTO, ALBERT S.; SOBRINHO, CLEYTON R.; MORENO, MAYARA F.; GILIO, GUSTAVO R.; et al. Adipocyte-specific mTORC2 deficiency impairs BAT and iWAT thermogenic capacity without affecting glucose uptake and energy expenditure in cold-acclimated mice. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 321, n. 5, p. E592-E605, . (16/23169-9, 19/25943-1, 17/23040-9, 15/13508-8, 17/17582-3, 18/03418-0, 17/17403-1, 17/12260-8, 19/01763-4, 19/17660-0, 15/19530-5, 20/09399-7, 19/04271-5, 12/25317-4)
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)
CHIMIN, PATRICIA; ANDRADE, MAYNARA L.; BELCHIOR, THIAGO; PASCHOAL, VIVIAN A.; MAGDALON, JULIANA; YAMASHITA, ALEX S.; CASTRO, ERIQUE; CASTOLDI, ANGELA; CHAVES-FILHO, ADRIANO B.; YOSHINAGA, MARCOS Y.; et al. Adipocyte mTORC1 deficiency promotes adipose tissue inflammation and NLRP3 inflammasome activation via oxidative stress and de novo ceramide synthesis. Journal of Lipid Research, v. 58, n. 9, p. 1797-1807, . (12/25317-4, 15/19530-5, 12/02270-2, 15/13508-8, 09/15354-7)

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