Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice
Laiglesia, Laura M. ; Escoté, Xavier ; Sáinz, Neira ; Felix-Soriano, Elisa ; Santamaría, Eva ; Collantes, María ; Fernández-Galilea, Marta ; Colón-Mesa, Ignacio ; Martínez-Fernández, Leyre ; Quesada-López, Tania ; Quesada-Vázquez, Sergio ; Rodríguez-Ortigosa, Carlos ; Arbones-Mainar, José M. ; Valverde, Ángela M. ; Martínez, J Alfredo ; Dalli, Jesmond ; Herrero, Laura ; Lorente-Cebrián, Silvia (Universidad de Zaragoza) ; Villarroya, Francesc ; Moreno-Aliaga, María J.
Resumen: Objective: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning.
Methods: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6−/−) mice.
Results: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6−/− mice.
Conclusions: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.
Idioma: Inglés
DOI: 10.1016/j.molmet.2023.101749
Año: 2023
Publicado en: Molecular Metabolism 74 (2023), 101749 [14 pp.]
ISSN: 2212-8778
Factor impacto SCIMAGO: 3.034 - Molecular Biology (Q1) - Cell Biology (Q1)
Financiación: info:eu-repo/grantAgreement/ES/MICINN /BFU2012-36089
Financiación: info:eu-repo/grantAgreement/ES/MICINN /BFU2015-65937-R
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-106982RB-I00
Tipo y forma: Article (Published version)
Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. If you remix, transform, or build upon the material, you may not distribute the modified material.
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Methods: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6−/−) mice.
Results: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6−/− mice.
Conclusions: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.
Idioma: Inglés
DOI: 10.1016/j.molmet.2023.101749
Año: 2023
Publicado en: Molecular Metabolism 74 (2023), 101749 [14 pp.]
ISSN: 2212-8778
Factor impacto SCIMAGO: 3.034 - Molecular Biology (Q1) - Cell Biology (Q1)
Financiación: info:eu-repo/grantAgreement/ES/MICINN /BFU2012-36089
Financiación: info:eu-repo/grantAgreement/ES/MICINN /BFU2015-65937-R
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-106982RB-I00
Tipo y forma: Article (Published version)
Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. If you remix, transform, or build upon the material, you may not distribute the modified material. Exportado de SIDERAL (2024-07-05-12:54:18)
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Record created 2023-09-21, last modified 2024-07-05