GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease

Autores
Baumann, Anja; Burger, Katharina; Brandt, Annette; Staltner, Raphaela; Jung, Finn; Rajcic, Dragana; Lorenzo Pisarello, Maria Jose; Bergheim, Ina
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and aims: Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved. Methods: Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662. Results: Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2−) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2− formation. Conclusion: In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.
Fil: Baumann, Anja. Universidad de Viena; Austria
Fil: Burger, Katharina. Universidad de Viena; Austria
Fil: Brandt, Annette. Universidad de Viena; Austria
Fil: Staltner, Raphaela. Universidad de Viena; Austria
Fil: Jung, Finn. Universidad de Viena; Austria
Fil: Rajcic, Dragana. Universidad de Viena; Austria
Fil: Lorenzo Pisarello, Maria Jose. Universidad de Viena; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina
Fil: Bergheim, Ina. Universidad de Viena; Austria
Materia
ENDOTOXIN
GLUCOSE TOLERANCE
INFLAMMATION
NON-ALCOHOLIC STEATOHEPATITIS
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/160203
Acceder
id CONICETDig_4a094d9cd1a632d138fc44d0233650c2
oai_identifier_str oai:ri.conicet.gov.ar:11336/160203
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver diseaseBaumann, AnjaBurger, KatharinaBrandt, AnnetteStaltner, RaphaelaJung, FinnRajcic, DraganaLorenzo Pisarello, Maria JoseBergheim, InaENDOTOXINGLUCOSE TOLERANCEINFLAMMATIONNON-ALCOHOLIC STEATOHEPATITISPEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMAhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Background and aims: Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved. Methods: Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662. Results: Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2−) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2− formation. Conclusion: In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.Fil: Baumann, Anja. Universidad de Viena; AustriaFil: Burger, Katharina. Universidad de Viena; AustriaFil: Brandt, Annette. Universidad de Viena; AustriaFil: Staltner, Raphaela. Universidad de Viena; AustriaFil: Jung, Finn. Universidad de Viena; AustriaFil: Rajcic, Dragana. Universidad de Viena; AustriaFil: Lorenzo Pisarello, Maria Jose. Universidad de Viena; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; ArgentinaFil: Bergheim, Ina. Universidad de Viena; AustriaElsevier2022-05-29info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/160203Baumann, Anja; Burger, Katharina; Brandt, Annette; Staltner, Raphaela; Jung, Finn; et al.; GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease; Elsevier; Metabolism-clinical And Experimental; 133; 29-5-2022; 1-110026-04951532-8600CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.metabol.2022.155233info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0026049522001111info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:37:46Zoai:ri.conicet.gov.ar:11336/160203instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:37:47.158CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
title GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
spellingShingle GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
Baumann, Anja
ENDOTOXIN
GLUCOSE TOLERANCE
INFLAMMATION
NON-ALCOHOLIC STEATOHEPATITIS
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA
title_short GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
title_full GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
title_fullStr GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
title_full_unstemmed GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
title_sort GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
dc.creator.none.fl_str_mv Baumann, Anja
Burger, Katharina
Brandt, Annette
Staltner, Raphaela
Jung, Finn
Rajcic, Dragana
Lorenzo Pisarello, Maria Jose
Bergheim, Ina
author Baumann, Anja
author_facet Baumann, Anja
Burger, Katharina
Brandt, Annette
Staltner, Raphaela
Jung, Finn
Rajcic, Dragana
Lorenzo Pisarello, Maria Jose
Bergheim, Ina
author_role author
author2 Burger, Katharina
Brandt, Annette
Staltner, Raphaela
Jung, Finn
Rajcic, Dragana
Lorenzo Pisarello, Maria Jose
Bergheim, Ina
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ENDOTOXIN
GLUCOSE TOLERANCE
INFLAMMATION
NON-ALCOHOLIC STEATOHEPATITIS
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA
topic ENDOTOXIN
GLUCOSE TOLERANCE
INFLAMMATION
NON-ALCOHOLIC STEATOHEPATITIS
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background and aims: Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved. Methods: Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662. Results: Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2−) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2− formation. Conclusion: In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.
Fil: Baumann, Anja. Universidad de Viena; Austria
Fil: Burger, Katharina. Universidad de Viena; Austria
Fil: Brandt, Annette. Universidad de Viena; Austria
Fil: Staltner, Raphaela. Universidad de Viena; Austria
Fil: Jung, Finn. Universidad de Viena; Austria
Fil: Rajcic, Dragana. Universidad de Viena; Austria
Fil: Lorenzo Pisarello, Maria Jose. Universidad de Viena; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina
Fil: Bergheim, Ina. Universidad de Viena; Austria
description Background and aims: Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved. Methods: Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662. Results: Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2−) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2− formation. Conclusion: In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.
publishDate 2022
dc.date.none.fl_str_mv 2022-05-29
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/160203
Baumann, Anja; Burger, Katharina; Brandt, Annette; Staltner, Raphaela; Jung, Finn; et al.; GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease; Elsevier; Metabolism-clinical And Experimental; 133; 29-5-2022; 1-11
0026-0495
1532-8600
CONICET Digital
CONICET
url http://hdl.handle.net/11336/160203
identifier_str_mv Baumann, Anja; Burger, Katharina; Brandt, Annette; Staltner, Raphaela; Jung, Finn; et al.; GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease; Elsevier; Metabolism-clinical And Experimental; 133; 29-5-2022; 1-11
0026-0495
1532-8600
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.metabol.2022.155233
info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0026049522001111
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/vnd.openxmlformats-officedocument.wordprocessingml.document
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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