Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice.
Por:
Laiglesia LM, Escoté X, Sáinz N, Felix-Soriano E, Santamaría E, Collantes M, Fernández-Galilea M, Colón-Mesa I, Martínez-Fernández L, Quesada T, Quesada-Vázquez S, Rodríguez-Ortigosa C, Arbones-Mainar JM, Valverde ÁM, Martínez JA, Dalli J, LAURA HERRERO RODRÍGUEZ, Lorente-Cebrián S, Villarroya-Gombau F and Moreno-Aliaga MJ
Publicada:
1 ago 2023
Ahead of Print:
2 jun 2023
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.
Filiaciones:
Laiglesia LM:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Escoté X:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, Reus, 43204 Spain
Sáinz N:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Felix-Soriano E:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Santamaría E:
Biomedical Research Centre for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
Division of Hepatology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Collantes M:
Department of Nuclear Medicine/ Translational Molecular Imaging Unit (UNIMTRA), Clínica Universidad de Navarra, Pamplona, 31008, Spain
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
Fernández-Galilea M:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
Colón-Mesa I:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Martínez-Fernández L:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Quesada T:
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Catalonia, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Quesada-Vázquez S:
Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, Reus, 43204 Spain
Rodríguez-Ortigosa C:
Biomedical Research Centre for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Division of Hepatology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Arbones-Mainar JM:
Adipocyte and Fat Biology Laboratory (AdipoFat), Instituto de Investigación Sanitaria Aragón, Instituto Aragonés de Ciencias de la Salud, Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain
Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Valverde ÁM:
Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), Madrid, Spain
Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Martínez JA:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Dalli J:
William Harvey Research Institute, Queen Mary University of London, London, UK
Center for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Center for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK
LAURA HERRERO RODRÍGUEZ:
Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain
Lorente-Cebrián S:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
Current address: Department of Pharmacology, Physiology, Legal and Forensic Medicine. Faculty of Health and Sport Science, University of Zaragoza, Zaragoza, Spain
Villarroya-Gombau F:
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Catalonia, Spain
Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Moreno-Aliaga MJ:
University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain
University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Electronic address:
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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