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.

• Document type: Journal article
• Source: Immunobiology; v. 222, n. 2, p. 261-271, FEB 2017.
• Web of Science Citations: 18

Abstract

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)

• FAPESP's process: 15/19530-5 - Involvement of the nutrient sensor mTOR in the development of obesity associated chronic metabolic diseases
• Grantee: William Tadeu Lara Festuccia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/10783-7 - mTOR complex 1 involvement in the control of macrophage function in the chronic inflammatory response associated with obesity and insulin resistance
• Grantee: Vivian Almeida Paschoal
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 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
• Grantee: William Tadeu Lara Festuccia
• Support Opportunities: Research Grants - Young Investigators Grants