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SUCNR1 Controls An Anti-inflammatory Program In Macrophages To Regulate The Metabolic Response To Obesity

N. Keiran, V. Ceperuelo-Mallafré, E. Calvo, M. Hernández-Alvarez, M. Ejarque, C. Núñez-Roa, D. Horrillo, E. Maymo-Masip, M. M. Rodríguez, R. Fradera, J. V. De la Rosa, R. Jorba, A. Megía, A. Zorzano, G. Medina-Gómez, C. Serena, A. Castrillo, J. Vendrell, S. Fernández‐Veledo
Published 2019 · Biology, Medicine

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Succinate 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.Succinate is a signaling metabolite sensed extracellularly by SUNCR1. Fernandez-Veledo and colleagues show that activation of SUCNR1 promotes an anti-inflammatory phenotype in adipose-tissue macrophages in lean mice and people.
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