O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea
Ano de defesa: | 2018 |
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Autor(a) principal: | |
Outros Autores: | |
Orientador(a): | |
Banca de defesa: | , , |
Tipo de documento: | Dissertação |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade do Estado do Rio de Janeiro
|
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Biociências
|
Departamento: |
Centro Biomédico::Faculdade de Ciências Médicas
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://www.bdtd.uerj.br/handle/1/17591 |
Resumo: | Our group demonstrated that high fat diet-induced obesity induces bone marrow proinflammatory microenvironment, which programs the mesenchymal stem cells (BM-MSC) to pro-adipogenic phenotype (Silva et al., 2016). However, it is unclear whether obesity affects the BM-MSC recruitment to different tissues. In this study, we evaluated the role of high fat diet-induced obesity on the BM-MSC recruitment. Male C57Bl/ 6J mice at 21 days of age were fed with a high-fat diet (45% Kcal from fat) during 16 weeks (HFD group). The control group (CHOW group) were fed with a normal fat diet. The HFD animals presented an increase of body mass, higher food intake and a significative increase of body fat mass with a consequent decrease of the lean mass. In addition, we observed a higher fasting glucose and serum insulin levels, accompanied by glucose and insulin intolerance. The analysis of epididymal adipose tissue showed an increase in the fat mass and the presence of hypertrophic adipocytes. We also observed a higher leptin and IL-10 production in the supernatant of epididymal adipose tissue. No changes were observed in the surface markers expression or in the adipogenic differentiation, however, the BM-MSC from the HFD group had a greater proliferative potential when compared to CHOW group. Obesity induced an increase in the frequency of blood MSC, but no difference was observed in the content of these cells in the epididymal adipose tissue. We also observed an increase of MSC migration (in vitro) in the absence of the chemotactic agent. The challenge of SDF-1α (10nM chemotactic agent) not induced the MSC migration in the HFD group. No change was observed in the expression of the SDF-1α receptor, CXCR4, but we detected an increase in the activation of the PI3K / AKT pathway and a higher actin cytoskeletal polymerization in MSCs from obese animals. Finally, we not observed changes in the gene expression of SDF-1α in epididymal and subcutaneous adipose tissues. Our data suggest that high fat diet-induced obesity promotes insulin resistance, regardless of the presence of metainflammation. In addition, we showed that obesity promotes a migratory profile of BM-MSC without affecting its frequency in the epididymal adipose tissue. (Protocol CEUA: 024/2017) |
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Silva, Simone Vargas dahttp://lattes.cnpq.br/5770301762451008Fidalgo, Thereza Christina Barjahttp://lattes.cnpq.br/7181616799746888Silva, Patrícia Cristina Lisbôa dahttp://lattes.cnpq.br/6704904748735082Reis, Marta Citelli doshttp://lattes.cnpq.br/1136248028072284Lindoso, Rafael Soareshttp://lattes.cnpq.br/2868007778082108http://lattes.cnpq.br/9680198783893605Ferreira, Agatha de Assisagathaferreira@globomail.com2022-04-19T14:10:58Z2018-02-26FERREIRA, Agatha de Assis. O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea. 2018. 66 f. Dissertação (Mestrado em Biociências) - Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2018.http://www.bdtd.uerj.br/handle/1/17591Our group demonstrated that high fat diet-induced obesity induces bone marrow proinflammatory microenvironment, which programs the mesenchymal stem cells (BM-MSC) to pro-adipogenic phenotype (Silva et al., 2016). However, it is unclear whether obesity affects the BM-MSC recruitment to different tissues. In this study, we evaluated the role of high fat diet-induced obesity on the BM-MSC recruitment. Male C57Bl/ 6J mice at 21 days of age were fed with a high-fat diet (45% Kcal from fat) during 16 weeks (HFD group). The control group (CHOW group) were fed with a normal fat diet. The HFD animals presented an increase of body mass, higher food intake and a significative increase of body fat mass with a consequent decrease of the lean mass. In addition, we observed a higher fasting glucose and serum insulin levels, accompanied by glucose and insulin intolerance. The analysis of epididymal adipose tissue showed an increase in the fat mass and the presence of hypertrophic adipocytes. We also observed a higher leptin and IL-10 production in the supernatant of epididymal adipose tissue. No changes were observed in the surface markers expression or in the adipogenic differentiation, however, the BM-MSC from the HFD group had a greater proliferative potential when compared to CHOW group. Obesity induced an increase in the frequency of blood MSC, but no difference was observed in the content of these cells in the epididymal adipose tissue. We also observed an increase of MSC migration (in vitro) in the absence of the chemotactic agent. The challenge of SDF-1α (10nM chemotactic agent) not induced the MSC migration in the HFD group. No change was observed in the expression of the SDF-1α receptor, CXCR4, but we detected an increase in the activation of the PI3K / AKT pathway and a higher actin cytoskeletal polymerization in MSCs from obese animals. Finally, we not observed changes in the gene expression of SDF-1α in epididymal and subcutaneous adipose tissues. Our data suggest that high fat diet-induced obesity promotes insulin resistance, regardless of the presence of metainflammation. In addition, we showed that obesity promotes a migratory profile of BM-MSC without affecting its frequency in the epididymal adipose tissue. (Protocol CEUA: 024/2017)Nosso grupo demonstrou que a obesidade induzida por dieta hiperlipídica promove um microambiente pró-inflamatório na medula óssea, o qual é responsável pelo comprometimento das células-tronco mesenquimais (CTMs) para um fenótipo pró-adipogênico (Silva et al., 2016). No entanto, não está claro se a obesidade afeta o recrutamento destas células para diversos tecidos. Neste estudo, avaliamos o papel da obesidade induzida por dieta hiperlipídica no recrutamento de CTMs isoladas da medula óssea. Camundongos C57Bl/6J com 21 dias de vida foram mantidos sob dieta hiperlipídica (45% de Kcal provenientes de gordura) por 16 semanas (grupo HFD). O grupo controle (grupo CHOW) consiste de animais que receberam dieta normolipídica durante o mesmo período. Os animais do grupo HFD apresentaram um aumento da massa corporal, maior consumo de ração e um aumento do percentual de gordura corporal com consequente diminuição da massa magra. Além disso, foi observada uma maior glicemia de jejum e insulinemia, acompanhados de intolerância à glicose e à insulina. A análise do tecido adiposo epididimal mostrou um aumento da massa e a presença de adipócitos hipertróficos, além de um aumento na secreção de leptina e IL-10 no sobrenadante deste tecido. Na caracterização das CTMs, não foram observadas alterações na expressão dos marcadores de superfície, nem na diferenciação adipogênica de CTMs entre os grupos, no entanto as células isoladas do grupo HFD apresentaram uma maior capacidade proliferativa quando comparadas ao grupo CHOW. A obesidade induziu um aumento na frequência das CTMs no sangue dos animais, porém não observamos diferença no conteúdo dessas células no tecido adiposo epididimal. A obesidade promoveu um aumento na migração (in vitro) das CTMs na ausência do estímulo quimiotático. O SDF-1α (estímulo quimiotático-10nM) não foi capaz de induzir a quimiotaxia das CTMs no grupo HFD. Em relação a via de sinalização envolvida na migração, não foram observadas alterações na expressão do receptor de SDF-1α, o CXCR4, porém evidenciamos um aumento da ativação da via PI3K/AKT e na polimerização do citoesqueleto de actina nas CTMs isoladas dos animais obesos. Finalmente, não foram detectadas alterações na expressão gênica de SDF-1α nos tecidos adiposos epididimal e subcutâneo entre os grupos. Até o momento, nossos dados sugerem que a obesidade induzida por dieta hiperlipídica promove um quadro de resistência à insulina, independente da presença de metainflamação. Além disso, a obesidade promove um perfil mais migratório das CTMs isoladas da medula óssea, contudo não altera a frequência dessas células no tecido adiposo epididimal. (Protocolo n° CEUA: 024/2017)Submitted by Heloísa CB/A (helobdtd@gmail.com) on 2022-04-19T14:10:58Z No. of bitstreams: 1 Agatha de Assis Ferreira.pdf: 1235839 bytes, checksum: 7e4f339f2f79bd68a917e0e79c40a2f4 (MD5)Made available in DSpace on 2022-04-19T14:10:58Z (GMT). No. of bitstreams: 1 Agatha de Assis Ferreira.pdf: 1235839 bytes, checksum: 7e4f339f2f79bd68a917e0e79c40a2f4 (MD5) Previous issue date: 2018-02-26Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPqapplication/pdfporUniversidade do Estado do Rio de JaneiroPrograma de Pós-Graduação em BiociênciasUERJBrasilCentro Biomédico::Faculdade de Ciências MédicasObesityAdipose tissueAdipogenesisCell migrationMesenchymal stem cellsObesidadeTecido adiposoAdipogêneseMigração celularCélulas-tronco mesenquimaisSDF-1αCIENCIAS BIOLOGICASO papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula ósseaThe role of obesity on the recruitment of bone marrow mesenchymal stem cellsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UERJinstname:Universidade do Estado do Rio de Janeiro (UERJ)instacron:UERJORIGINALDissertação - Agatha de Assis Ferreira - 2018 - Completa.pdfDissertação - Agatha de Assis Ferreira - 2018 - Completa.pdfapplication/pdf1235839http://www.bdtd.uerj.br/bitstream/1/17591/2/Disserta%C3%A7%C3%A3o+-+Agatha+de+Assis+Ferreira+-+2018+-+Completa.pdf7e4f339f2f79bd68a917e0e79c40a2f4MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82123http://www.bdtd.uerj.br/bitstream/1/17591/1/license.txte5502652da718045d7fcd832b79fca29MD511/175912024-02-26 11:39:25.596oai:www.bdtd.uerj.br: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Biblioteca Digital de Teses e Dissertaçõeshttp://www.bdtd.uerj.br/PUBhttps://www.bdtd.uerj.br:8443/oai/requestbdtd.suporte@uerj.bropendoar:29032024-02-26T14:39:25Biblioteca Digital de Teses e Dissertações da UERJ - Universidade do Estado do Rio de Janeiro (UERJ)false |
dc.title.por.fl_str_mv |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea |
dc.title.alternative.eng.fl_str_mv |
The role of obesity on the recruitment of bone marrow mesenchymal stem cells |
title |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea |
spellingShingle |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea Ferreira, Agatha de Assis Obesity Adipose tissue Adipogenesis Cell migration Mesenchymal stem cells Obesidade Tecido adiposo Adipogênese Migração celular Células-tronco mesenquimais SDF-1α CIENCIAS BIOLOGICAS |
title_short |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea |
title_full |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea |
title_fullStr |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea |
title_full_unstemmed |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea |
title_sort |
O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea |
author |
Ferreira, Agatha de Assis |
author_facet |
Ferreira, Agatha de Assis agathaferreira@globomail.com |
author_role |
author |
author2 |
agathaferreira@globomail.com |
author2_role |
author |
dc.contributor.advisor1.fl_str_mv |
Silva, Simone Vargas da |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/5770301762451008 |
dc.contributor.advisor-co1.fl_str_mv |
Fidalgo, Thereza Christina Barja |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/7181616799746888 |
dc.contributor.referee1.fl_str_mv |
Silva, Patrícia Cristina Lisbôa da |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/6704904748735082 |
dc.contributor.referee2.fl_str_mv |
Reis, Marta Citelli dos |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/1136248028072284 |
dc.contributor.referee3.fl_str_mv |
Lindoso, Rafael Soares |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/2868007778082108 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/9680198783893605 |
dc.contributor.author.fl_str_mv |
Ferreira, Agatha de Assis agathaferreira@globomail.com |
contributor_str_mv |
Silva, Simone Vargas da Fidalgo, Thereza Christina Barja Silva, Patrícia Cristina Lisbôa da Reis, Marta Citelli dos Lindoso, Rafael Soares |
dc.subject.eng.fl_str_mv |
Obesity Adipose tissue Adipogenesis Cell migration Mesenchymal stem cells |
topic |
Obesity Adipose tissue Adipogenesis Cell migration Mesenchymal stem cells Obesidade Tecido adiposo Adipogênese Migração celular Células-tronco mesenquimais SDF-1α CIENCIAS BIOLOGICAS |
dc.subject.por.fl_str_mv |
Obesidade Tecido adiposo Adipogênese Migração celular Células-tronco mesenquimais SDF-1α |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS |
description |
Our group demonstrated that high fat diet-induced obesity induces bone marrow proinflammatory microenvironment, which programs the mesenchymal stem cells (BM-MSC) to pro-adipogenic phenotype (Silva et al., 2016). However, it is unclear whether obesity affects the BM-MSC recruitment to different tissues. In this study, we evaluated the role of high fat diet-induced obesity on the BM-MSC recruitment. Male C57Bl/ 6J mice at 21 days of age were fed with a high-fat diet (45% Kcal from fat) during 16 weeks (HFD group). The control group (CHOW group) were fed with a normal fat diet. The HFD animals presented an increase of body mass, higher food intake and a significative increase of body fat mass with a consequent decrease of the lean mass. In addition, we observed a higher fasting glucose and serum insulin levels, accompanied by glucose and insulin intolerance. The analysis of epididymal adipose tissue showed an increase in the fat mass and the presence of hypertrophic adipocytes. We also observed a higher leptin and IL-10 production in the supernatant of epididymal adipose tissue. No changes were observed in the surface markers expression or in the adipogenic differentiation, however, the BM-MSC from the HFD group had a greater proliferative potential when compared to CHOW group. Obesity induced an increase in the frequency of blood MSC, but no difference was observed in the content of these cells in the epididymal adipose tissue. We also observed an increase of MSC migration (in vitro) in the absence of the chemotactic agent. The challenge of SDF-1α (10nM chemotactic agent) not induced the MSC migration in the HFD group. No change was observed in the expression of the SDF-1α receptor, CXCR4, but we detected an increase in the activation of the PI3K / AKT pathway and a higher actin cytoskeletal polymerization in MSCs from obese animals. Finally, we not observed changes in the gene expression of SDF-1α in epididymal and subcutaneous adipose tissues. Our data suggest that high fat diet-induced obesity promotes insulin resistance, regardless of the presence of metainflammation. In addition, we showed that obesity promotes a migratory profile of BM-MSC without affecting its frequency in the epididymal adipose tissue. (Protocol CEUA: 024/2017) |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018-02-26 |
dc.date.accessioned.fl_str_mv |
2022-04-19T14:10:58Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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masterThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
FERREIRA, Agatha de Assis. O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea. 2018. 66 f. Dissertação (Mestrado em Biociências) - Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2018. |
dc.identifier.uri.fl_str_mv |
http://www.bdtd.uerj.br/handle/1/17591 |
identifier_str_mv |
FERREIRA, Agatha de Assis. O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea. 2018. 66 f. Dissertação (Mestrado em Biociências) - Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2018. |
url |
http://www.bdtd.uerj.br/handle/1/17591 |
dc.language.iso.fl_str_mv |
por |
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por |
dc.rights.driver.fl_str_mv |
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openAccess |
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dc.publisher.none.fl_str_mv |
Universidade do Estado do Rio de Janeiro |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Biociências |
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UERJ |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Centro Biomédico::Faculdade de Ciências Médicas |
publisher.none.fl_str_mv |
Universidade do Estado do Rio de Janeiro |
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