mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function.
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.
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Vivian A
VA
Paschoal
Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Mariane T
MT
Amano
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Thiago
T
Belchior
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Juliana
J
Magdalon
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Patricia
P
Chimin
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Maynara L
ML
Andrade
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Milene
M
Ortiz-Silva
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Érique
É
Castro
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Alex S
AS
Yamashita
Department of Cell Biology and Development, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
José Cesar
JC
Rosa Neto
Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil.
Niels O
NO
Câmara
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508000, Brazil. Electronic address: william.festuccia@usp.br.
William T
WT
Festuccia
D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015434:Panniculitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D020123:Sirolimus / Q000494:pharmacology
D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D000076222:Mechanistic Target of Rapamycin Complex 1; D005947:Glucose; D020123:Sirolimus
Adipose tissue inflammation; Cytokines; Macrophages; Obesity; Rapamycin; mTOR