Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

Objective Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is nec...

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Detalles Bibliográficos
Autores: Escalona Garrido, Carmen, Martínez Valverde, Ángela María
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/112136
Acceso en línea:https://hdl.handle.net/20.500.14352/112136
Access Level:acceso abierto
Palabra clave:576
Brown adipose tissue
Inflammation
Insulin resistance
Sirtuin 1
Triiodothyronine
Uncoupling protein-1
Ciencias Biomédicas
Biología molecular (Biología)
24 Ciencias de la Vida
2415 Biología Molecular
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oai_identifier_str oai:docta.ucm.es:20.500.14352/112136
network_acronym_str ES
network_name_str España
repository_id_str
spelling Moderate SIRT1 overexpression protects against brown adipose tissue inflammationEscalona Garrido, CarmenMartínez Valverde, Ángela María576Brown adipose tissueInflammationInsulin resistanceSirtuin 1TriiodothyronineUncoupling protein-1Ciencias BiomédicasBiología molecular (Biología)24 Ciencias de la Vida2415 Biología MolecularObjective Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods The effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results BAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T3) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. Conclusions This study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.ElsevierUniversidad Complutense de Madrid20202020-11-2920202020-11-29journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/112136reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengMinisterio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 PLAN ESTATAL DE INVESTIGACIÓN CIENTÍFICA Y TÉCNICA Y DE INNOVACIÓN 2017 -2020 RTI2018-094052-B-100Comunidad de Madrid http://dx.doi.org/10.13039/100012818 S2017 BMD-3684open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1121362026-06-02T12:44:21Z
dc.title.none.fl_str_mv Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
title Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
spellingShingle Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
Escalona Garrido, Carmen
576
Brown adipose tissue
Inflammation
Insulin resistance
Sirtuin 1
Triiodothyronine
Uncoupling protein-1
Ciencias Biomédicas
Biología molecular (Biología)
24 Ciencias de la Vida
2415 Biología Molecular
title_short Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
title_full Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
title_fullStr Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
title_full_unstemmed Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
title_sort Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
dc.creator.none.fl_str_mv Escalona Garrido, Carmen
Martínez Valverde, Ángela María
author Escalona Garrido, Carmen
author_facet Escalona Garrido, Carmen
Martínez Valverde, Ángela María
author_role author
author2 Martínez Valverde, Ángela María
author2_role author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 576
Brown adipose tissue
Inflammation
Insulin resistance
Sirtuin 1
Triiodothyronine
Uncoupling protein-1
Ciencias Biomédicas
Biología molecular (Biología)
24 Ciencias de la Vida
2415 Biología Molecular
topic 576
Brown adipose tissue
Inflammation
Insulin resistance
Sirtuin 1
Triiodothyronine
Uncoupling protein-1
Ciencias Biomédicas
Biología molecular (Biología)
24 Ciencias de la Vida
2415 Biología Molecular
description Objective Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods The effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results BAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T3) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. Conclusions This study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-11-29
2020
2020-11-29
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/112136
url https://hdl.handle.net/20.500.14352/112136
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 PLAN ESTATAL DE INVESTIGACIÓN CIENTÍFICA Y TÉCNICA Y DE INNOVACIÓN 2017 -2020 RTI2018-094052-B-100
Comunidad de Madrid http://dx.doi.org/10.13039/100012818 S2017 BMD-3684
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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