mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function

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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 ; Camara, Niels O. ; Festuccia, William T.

• Tipo de documento: Artigo Científico
• Fonte: Immunobiology; v. 222, n. 2, p. 261-271, FEB 2017.
• Citações Web of Science: 17

Resumo

Genetic- and diet-induced obesity and insulin resistance are associated with an increase in mechanistic target of rapamycin complex (mTORC) I activity in adipose tissue. We investigated herein the effects of pharmacological mTORC1 inhibition in the development of adipose tissue inflammation induced by high-fat diet (HFD) feeding, as well as in the polarization, metabolism and function of bone marrow-derived macrophages (BMDM). For this, C57BL/6J mice fed with a standard chow diet or a HFD (60% of calories from fat) and treated with either vehicle (0.1% Me2SO, 0.2% methylcellulose) or rapamycin (2 mg/kg/day, gavage) during 30 days were evaluated for body weight, adiposity, glucose tolerance and adipose tissue inflammation. Although rapamycin did not affect the increase in body weight and adiposity, it exacerbated the glucose intolerance and adipose tissue inflammation induced by HFD feeding, as evidenced by the increased adipose tissue percentage of M1 macrophages, naive and activated cytotoxic T lymphocytes, and mRNA levels of proinflammatory molecules, such as TNF-alpha, IL-6 and MCP-1. In BMDM in vitro, pharmacological mTORC1 inhibition induced phosphorylation of NF kappa B p65 and spontaneous polarization of macrophages to a proinflammatory M1 profile, while it impaired M2 polarization induced by IL-4 + IL-13, glycolysis and phagocytosis. Altogether, these findings indicate that mTORC1 activity is an important determinant of adipose tissue inflammatory profile and macrophage plasticity, metabolism and function. (C) 2016 Elsevier GmbH. All rights reserved. (AU)

• Processo FAPESP: 11/10783-7 - Envolvimento do complexo 1 da mTOR no controle da função de macrófagos durante resposta inflamatória crônica associada a obesidade e resistência à insulina
• Beneficiário: Vivian Almeida Paschoal
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/52191-6 - Envolvimento dos sensores de nutrientes mTOR e PPARgama no início, manutenção e término da inflamação associada à obesidade e resistência à insulina
• Beneficiário: William Tadeu Lara Festuccia
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/15354-7 - Envolvimento do tecido adiposo no desenvolvimento da obesidade e patologias associadas: investigação dos mecanismos moleculares e busca de novas alternativas terapêuticas
• Beneficiário: William Tadeu Lara Festuccia
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
• Processo FAPESP: 12/02270-2 - Novos mecanismos celulares, moleculares e imunológicos das lesões renais agudas e crônicas: busca por novas estratégias terapêuticas
• Beneficiário: Niels Olsen Saraiva Câmara
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/19530-5 - Caracterização do envolvimento do sensor de nutrientes mTOR no desenvolvimento de doenças metabólicas crônicas associadas à obesidade
• Beneficiário: William Tadeu Lara Festuccia
• Linha de fomento: Auxílio à Pesquisa - Temático