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...
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Veröffentlicht in: | Immunobiology (1979) 2017-02, Vol.222 (2), p.261-271 |
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creator | Paschoal, Vivian A Amano, Mariane T Belchior, Thiago Magdalon, Juliana Chimin, Patricia Andrade, Maynara L Ortiz-Silva, Milene Castro, Érique Yamashita, Alex S Rosa Neto, José Cesar Câmara, Niels O Festuccia, William T |
description | 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% Me2 SO, 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-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. |
doi_str_mv | 10.1016/j.imbio.2016.09.014 |
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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% Me2 SO, 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-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.</description><identifier>ISSN: 0171-2985</identifier><identifier>EISSN: 1878-3279</identifier><identifier>DOI: 10.1016/j.imbio.2016.09.014</identifier><identifier>PMID: 27692982</identifier><language>eng</language><publisher>Netherlands: Elsevier GmbH</publisher><subject>Adipose tissue inflammation ; Advanced Basic Science ; Allergy and Immunology ; Animals ; Biomarkers ; Cytokines ; Cytokines - metabolism ; Glucose - metabolism ; Immunophenotyping ; Inflammation Mediators - metabolism ; Leukocytes - immunology ; Leukocytes - metabolism ; Leukocytes - pathology ; Macrophages ; Macrophages - drug effects ; Macrophages - immunology ; Macrophages - metabolism ; Macrophages, Peritoneal - drug effects ; Macrophages, Peritoneal - immunology ; Macrophages, Peritoneal - metabolism ; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; mTOR ; Obesity ; Obesity - immunology ; Obesity - metabolism ; Obesity - pathology ; Panniculitis - immunology ; Panniculitis - metabolism ; Panniculitis - pathology ; Phenotype ; Rapamycin ; Sirolimus - pharmacology</subject><ispartof>Immunobiology (1979), 2017-02, Vol.222 (2), p.261-271</ispartof><rights>Elsevier GmbH</rights><rights>2016 Elsevier GmbH</rights><rights>Copyright © 2016 Elsevier GmbH. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-8e0c43fdc35150d98b649adaf0accca759d57af15beacf6e926493084269f1573</citedby><cites>FETCH-LOGICAL-c414t-8e0c43fdc35150d98b649adaf0accca759d57af15beacf6e926493084269f1573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.imbio.2016.09.014$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3552,27931,27932,46002</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27692982$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Paschoal, Vivian A</creatorcontrib><creatorcontrib>Amano, Mariane T</creatorcontrib><creatorcontrib>Belchior, Thiago</creatorcontrib><creatorcontrib>Magdalon, Juliana</creatorcontrib><creatorcontrib>Chimin, Patricia</creatorcontrib><creatorcontrib>Andrade, Maynara L</creatorcontrib><creatorcontrib>Ortiz-Silva, Milene</creatorcontrib><creatorcontrib>Castro, Érique</creatorcontrib><creatorcontrib>Yamashita, Alex S</creatorcontrib><creatorcontrib>Rosa Neto, José Cesar</creatorcontrib><creatorcontrib>Câmara, Niels O</creatorcontrib><creatorcontrib>Festuccia, William T</creatorcontrib><title>mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function</title><title>Immunobiology (1979)</title><addtitle>Immunobiology</addtitle><description>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% Me2 SO, 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-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.</description><subject>Adipose tissue inflammation</subject><subject>Advanced Basic Science</subject><subject>Allergy and Immunology</subject><subject>Animals</subject><subject>Biomarkers</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Glucose - metabolism</subject><subject>Immunophenotyping</subject><subject>Inflammation Mediators - metabolism</subject><subject>Leukocytes - immunology</subject><subject>Leukocytes - metabolism</subject><subject>Leukocytes - pathology</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Macrophages, Peritoneal - drug effects</subject><subject>Macrophages, Peritoneal - immunology</subject><subject>Macrophages, Peritoneal - metabolism</subject><subject>Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Obese</subject><subject>mTOR</subject><subject>Obesity</subject><subject>Obesity - immunology</subject><subject>Obesity - metabolism</subject><subject>Obesity - pathology</subject><subject>Panniculitis - immunology</subject><subject>Panniculitis - metabolism</subject><subject>Panniculitis - pathology</subject><subject>Phenotype</subject><subject>Rapamycin</subject><subject>Sirolimus - pharmacology</subject><issn>0171-2985</issn><issn>1878-3279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks-OFCEQxonRuLOrT2BiOHrpFpr-x0ETM1HXZJNNdD2Taqh2GBtooVudR_CtZWZWD148Eaq-XxXUV4Q846zkjLcv96V1gw1llS8lkyXj9QOy4X3XF6Lq5EOyYbzjRSX75oJcprRnjMuq6x-Ti6prZY5XG_LL3d1-3HJq_c4OdrHB0x922dEIM7iDtp7iT9AYB1gwUTB2DgnpYlNaMUPjBM7BCcvSMGBOOquRgjfUZFXQ9kQ60DHMO_iCdN6hD8thRjrG4Oi4en0s8IQ8GmFK-PT-vCKf3729214XN7fvP2zf3BS65vVS9Mh0LUajRcMbZmQ_tLUEAyMDrTV0jTRNByNvBgQ9tiirnBesr6tW5mgnrsiLc905hm8rpkU5mzROE3gMa1K8F02u3UmZpeIszW9PKeKo5mgdxIPiTB09UHt18kAdPVBMquxBpp7fN1gHh-Yv82foWfDqLMD8ze8Wo0raotdobES9KBPsfxq8_ofXk_VWw_QVD5j2YY0-T1BxlSrF1KfjGhy3gLeCiZ4L8RsQ67Fj</recordid><startdate>20170201</startdate><enddate>20170201</enddate><creator>Paschoal, Vivian A</creator><creator>Amano, Mariane T</creator><creator>Belchior, Thiago</creator><creator>Magdalon, Juliana</creator><creator>Chimin, Patricia</creator><creator>Andrade, Maynara L</creator><creator>Ortiz-Silva, Milene</creator><creator>Castro, Érique</creator><creator>Yamashita, Alex S</creator><creator>Rosa Neto, José Cesar</creator><creator>Câmara, Niels O</creator><creator>Festuccia, William T</creator><general>Elsevier GmbH</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20170201</creationdate><title>mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function</title><author>Paschoal, Vivian A ; Amano, Mariane T ; Belchior, Thiago ; Magdalon, Juliana ; Chimin, Patricia ; Andrade, Maynara L ; Ortiz-Silva, Milene ; Castro, Érique ; Yamashita, Alex S ; Rosa Neto, José Cesar ; Câmara, Niels O ; Festuccia, William T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c414t-8e0c43fdc35150d98b649adaf0accca759d57af15beacf6e926493084269f1573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adipose tissue inflammation</topic><topic>Advanced Basic Science</topic><topic>Allergy and Immunology</topic><topic>Animals</topic><topic>Biomarkers</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Glucose - metabolism</topic><topic>Immunophenotyping</topic><topic>Inflammation Mediators - metabolism</topic><topic>Leukocytes - immunology</topic><topic>Leukocytes - metabolism</topic><topic>Leukocytes - pathology</topic><topic>Macrophages</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - immunology</topic><topic>Macrophages - metabolism</topic><topic>Macrophages, Peritoneal - drug effects</topic><topic>Macrophages, Peritoneal - immunology</topic><topic>Macrophages, Peritoneal - metabolism</topic><topic>Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Obese</topic><topic>mTOR</topic><topic>Obesity</topic><topic>Obesity - immunology</topic><topic>Obesity - metabolism</topic><topic>Obesity - pathology</topic><topic>Panniculitis - immunology</topic><topic>Panniculitis - metabolism</topic><topic>Panniculitis - pathology</topic><topic>Phenotype</topic><topic>Rapamycin</topic><topic>Sirolimus - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Paschoal, Vivian A</creatorcontrib><creatorcontrib>Amano, Mariane T</creatorcontrib><creatorcontrib>Belchior, Thiago</creatorcontrib><creatorcontrib>Magdalon, Juliana</creatorcontrib><creatorcontrib>Chimin, Patricia</creatorcontrib><creatorcontrib>Andrade, Maynara L</creatorcontrib><creatorcontrib>Ortiz-Silva, Milene</creatorcontrib><creatorcontrib>Castro, Érique</creatorcontrib><creatorcontrib>Yamashita, Alex S</creatorcontrib><creatorcontrib>Rosa Neto, José Cesar</creatorcontrib><creatorcontrib>Câmara, Niels O</creatorcontrib><creatorcontrib>Festuccia, William T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Immunobiology (1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Paschoal, Vivian A</au><au>Amano, Mariane T</au><au>Belchior, Thiago</au><au>Magdalon, Juliana</au><au>Chimin, Patricia</au><au>Andrade, Maynara L</au><au>Ortiz-Silva, Milene</au><au>Castro, Érique</au><au>Yamashita, Alex S</au><au>Rosa Neto, José Cesar</au><au>Câmara, Niels O</au><au>Festuccia, William T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function</atitle><jtitle>Immunobiology (1979)</jtitle><addtitle>Immunobiology</addtitle><date>2017-02-01</date><risdate>2017</risdate><volume>222</volume><issue>2</issue><spage>261</spage><epage>271</epage><pages>261-271</pages><issn>0171-2985</issn><eissn>1878-3279</eissn><abstract>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% Me2 SO, 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-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.</abstract><cop>Netherlands</cop><pub>Elsevier GmbH</pub><pmid>27692982</pmid><doi>10.1016/j.imbio.2016.09.014</doi><tpages>11</tpages></addata></record> |
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subjects | Adipose tissue inflammation Advanced Basic Science Allergy and Immunology Animals Biomarkers Cytokines Cytokines - metabolism Glucose - metabolism Immunophenotyping Inflammation Mediators - metabolism Leukocytes - immunology Leukocytes - metabolism Leukocytes - pathology Macrophages Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Macrophages, Peritoneal - drug effects Macrophages, Peritoneal - immunology Macrophages, Peritoneal - metabolism Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors Mice Mice, Inbred C57BL Mice, Obese mTOR Obesity Obesity - immunology Obesity - metabolism Obesity - pathology Panniculitis - immunology Panniculitis - metabolism Panniculitis - pathology Phenotype Rapamycin Sirolimus - pharmacology |
title | mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function |
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