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...
| Authors: | ; |
|---|---|
| Format: | Article |
| Publication date: | 2020 |
| Country: | España |
| Institution: | Universidad Complutense de Madrid (UCM) |
| Repository: | Docta Complutense |
| Language: | English |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/112136 |
| Online Access: | https://hdl.handle.net/20.500.14352/112136 |
| Access Level: | Open access |
| Keyword: | 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 |
| _version_ | 1878742592700547072 |
|---|---|
| author | Escalona Garrido, Carmen |
| author2 | Martínez Valverde, Ángela María |
| author2_role | author |
| author_browse | Escalona Garrido, Carmen Martínez Valverde, Ángela María |
| author_facet | Escalona Garrido, Carmen Martínez Valverde, Ángela María |
| author_role | author |
| collection | Docta Complutense |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_f8bbeff86214a5db232f98e8e809c2e2 |
| institution | Universidad Complutense de Madrid (UCM) |
| instname_str | Universidad Complutense de Madrid (UCM) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:docta.ucm.es:20.500.14352/112136 |
| publishDate | 2020 |
| publishDateSort | 2020 |
| publisher | Elsevier |
| publisherStr | Elsevier |
| reponame_str | Docta Complutense |
| spelling | Moderate SIRT1 overexpression protects against brown adipose tissue inflammation Escalona Garrido, Carmen Martínez Valverde, Ángela María 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 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. Elsevier https://hdl.handle.net/20.500.14352/112136 |
| 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 | 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_short | Moderate SIRT1 overexpression protects against brown adipose tissue inflammation |
| title_sort | Moderate SIRT1 overexpression protects against brown adipose tissue inflammation |
| 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 |
| topic_facet | 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 |
| url | https://hdl.handle.net/20.500.14352/112136 |