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 de...

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Autores: Escalona-Garrido, Carmen, Vázquez, Patricia, Mera Nanín, Paula, Zagmutt Caroxa, Sebastián, García-Casarrubios, Ester, Montero-Pedrazuela, Ana, Rey-Stolle, Fernanda, Guadaño-Ferraz, Ana, Rupérez, Francisco J., Serra i Cucurull, Dolors, Herrero Rodríguez, Laura, Obregón, Maria Jesús, Valverde, Ángela M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/173877
Acceso en línea:https://hdl.handle.net/2445/173877
Access Level:acceso abierto
Palabra clave:Teixit adipós
Obesitat
Resistència a la insulina
Adipose tissues
Obesity
Insulin resistance
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spelling Moderate SIRT1 overexpression protects against brown adipose tissue inflammationEscalona-Garrido, CarmenVázquez, PatriciaMera Nanín, PaulaZagmutt Caroxa, SebastiánGarcía-Casarrubios, EsterMontero-Pedrazuela, AnaRey-Stolle, FernandaGuadaño-Ferraz, AnaRupérez, Francisco J.Serra i Cucurull, DolorsHerrero Rodríguez, LauraObregón, Maria JesúsValverde, Ángela M.Teixit adipósObesitatResistència a la insulinaAdipose tissuesObesityInsulin resistanceObjective: 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 demanding to find strategies to protect BAT against the effects of inflammation in energy balance. In this study we have explored the impact of moderate Sirtuin 1 (SIRT1) overexpression in insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods: The effect of inflammation in BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies in differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophagederived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), as well as norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results: BAT from db/db mice was susceptible to metabolic inflammation manifested by 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 lean WT mice upon LPS injection. By contrast, BAT from mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPSinduced activation of pro-inflammatory signaling, insulin resistance and defective thermogenicrelated responses upon cold exposure. Importantly, the drop of triiodothyronine (T3) levels both in circulation and intra-BAT after exposure of WT mice to LPS and cold was markedly attenuated in SIRT1Tg+ mice. In vitro experiments in BA from the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophagederived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. Conclusion: This study has unraveled the benefit of moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by inflammation in BAT. Our results have potential therapeutic value proposing combinatorial therapies of BATspecific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.Elsevier GmbH2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/173877Articles publicats en revistes (Bioquímica i Fisiologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.molmet.2020.101097Molecular Metabolism, 2020https://doi.org/10.1016/j.molmet.2020.101097cc-by-nc-nd (c) Escalona-Garrido, Carmen et al., 2020http://creativecommons.org/licenses/by-nc-nd/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1738772026-05-27T06:46:51Z
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
Teixit adipós
Obesitat
Resistència a la insulina
Adipose tissues
Obesity
Insulin resistance
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
Vázquez, Patricia
Mera Nanín, Paula
Zagmutt Caroxa, Sebastián
García-Casarrubios, Ester
Montero-Pedrazuela, Ana
Rey-Stolle, Fernanda
Guadaño-Ferraz, Ana
Rupérez, Francisco J.
Serra i Cucurull, Dolors
Herrero Rodríguez, Laura
Obregón, Maria Jesús
Valverde, Ángela M.
author Escalona-Garrido, Carmen
author_facet Escalona-Garrido, Carmen
Vázquez, Patricia
Mera Nanín, Paula
Zagmutt Caroxa, Sebastián
García-Casarrubios, Ester
Montero-Pedrazuela, Ana
Rey-Stolle, Fernanda
Guadaño-Ferraz, Ana
Rupérez, Francisco J.
Serra i Cucurull, Dolors
Herrero Rodríguez, Laura
Obregón, Maria Jesús
Valverde, Ángela M.
author_role author
author2 Vázquez, Patricia
Mera Nanín, Paula
Zagmutt Caroxa, Sebastián
García-Casarrubios, Ester
Montero-Pedrazuela, Ana
Rey-Stolle, Fernanda
Guadaño-Ferraz, Ana
Rupérez, Francisco J.
Serra i Cucurull, Dolors
Herrero Rodríguez, Laura
Obregón, Maria Jesús
Valverde, Ángela M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Teixit adipós
Obesitat
Resistència a la insulina
Adipose tissues
Obesity
Insulin resistance
topic Teixit adipós
Obesitat
Resistència a la insulina
Adipose tissues
Obesity
Insulin resistance
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 demanding to find strategies to protect BAT against the effects of inflammation in energy balance. In this study we have explored the impact of moderate Sirtuin 1 (SIRT1) overexpression in insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods: The effect of inflammation in BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies in differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophagederived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), as well as norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results: BAT from db/db mice was susceptible to metabolic inflammation manifested by 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 lean WT mice upon LPS injection. By contrast, BAT from mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPSinduced activation of pro-inflammatory signaling, insulin resistance and defective thermogenicrelated responses upon cold exposure. Importantly, the drop of triiodothyronine (T3) levels both in circulation and intra-BAT after exposure of WT mice to LPS and cold was markedly attenuated in SIRT1Tg+ mice. In vitro experiments in BA from the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophagederived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. Conclusion: This study has unraveled the benefit of moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by inflammation in BAT. Our results have potential therapeutic value proposing combinatorial therapies of BATspecific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/173877
url https://hdl.handle.net/2445/173877
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.molmet.2020.101097
Molecular Metabolism, 2020
https://doi.org/10.1016/j.molmet.2020.101097
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Escalona-Garrido, Carmen et al., 2020
http://creativecommons.org/licenses/by-nc-nd/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Escalona-Garrido, Carmen et al., 2020
http://creativecommons.org/licenses/by-nc-nd/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier GmbH
publisher.none.fl_str_mv Elsevier GmbH
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Fisiologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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