Keiran, NoeliaCeperuelo-Mallafré, VictoriaCalvo, EnriqueHernández-Alvarez, María isabelEjarque, MiriamNúñez-Roa, CatalinaHormillo, DanielMaymó-Masip, ElsaRodriguez, M MarFradera, Rosade la Rosa, Juan VladimirJorba, RosaMegia, AnaZorzano, AntonioMedina-Gomez, GemaSerena, CarolinaCastrillo, AntonioVendrell, JoanFernández-Veledo, Sonia2023-12-212023-12-212019-05Keiran N, Ceperuelo-Mallafré V, Calvo E, Hernández-Alvarez MI, Ejarque M, Núñez-Roa C, Horrillo D, Maymó-Masip E, Rodríguez MM, Fradera R, de la Rosa JV, Jorba R, Megia A, Zorzano A, Medina-Gómez G, Serena C, Castrillo A, Vendrell J, Fernández-Veledo S. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. Nat Immunol. 2019 May;20(5):581-592. doi: 10.1038/s41590-019-0372-7. Epub 2019 Apr 8. PMID: 30962591.1529-2908https://hdl.handle.net/10115/27621Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.engAdipose Tissue / drug effects Adipose Tissue / immunology Adipose Tissue / metabolism Animals Cells, Cultured Cytokines / genetics Cytokines / immunology Cytokines / metabolism Gene Expression Profiling / methods Humans Inflammation / genetics Inflammation / immunology* Inflammation / metabolism Macrophages / immunology* Macrophages / metabolism Male Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Obesity / genetics Obesity / immunology* Obesity / metabolism Receptors, G-Protein-Coupled / deficiency Receptors, G-Protein-Coupled / genetics Receptors, G-Protein-Coupled / immunology* Succinic Acid / immunology Succinic Acid / metabolism Succinic Acid / pharmacology THP-1 Cellsinfo:eu-repo/semantics/articleDOI: 10.1038/s41590-019-0372-7info:eu-repo/semantics/openAccess