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

Abstract

Genetic- and diet-induced obesity and insulin resistance are associated with an increase in mechanistic target of rapamycin complex (mTORC) 1 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 (2mg/kg/ day, gavage) during 30days 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-α, IL-6 and MCP-1. In BMDM in vitro, pharmacological mTORC1 inhibition induced phosphorylation of NFκB 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.

• Authors: Vivian A Paschoal, Mariane T Amano, Thiago Belchior, Juliana Magdalon, Patricia Chimin, Maynara L Andrade, Milene Ortiz-Silva, Érique Castro, Alex S Yamashita, José Cesar Rosa Neto, Niels O Câmara, William T Festuccia
• Journal: Immunobiology (Immunobiology) Vol. 222 Issue 2 Pg. 261-271 (02 2017) ISSN: 1878-3279 [Electronic] Netherlands
• PMID: 27692982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier GmbH. All rights reserved.

Chemical References

• Biomarkers
• Cytokines
• Inflammation Mediators
• Mechanistic Target of Rapamycin Complex 1
• Glucose
• Sirolimus

Topics

• Animals
• Biomarkers
• Cytokines (metabolism)
• Glucose (metabolism)
• Immunophenotyping
• Inflammation Mediators (metabolism)
• Leukocytes (immunology, metabolism, pathology)
• Macrophages (drug effects, immunology, metabolism)
• Macrophages, Peritoneal (drug effects, immunology, metabolism)
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (immunology, metabolism, pathology)
• Panniculitis (immunology, metabolism, pathology)
• Phenotype
• Sirolimus (pharmacology)