SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity

• Published in: Nature immunology Vol. 20; no. 5; pp. 581 - 592
• Main Authors: Keiran, Noelia, Ceperuelo-Mallafré, Victoria, Calvo, Enrique, Hernández-Alvarez, Maria Isabel, Ejarque, Miriam, Núñez-Roa, Catalina, Horrillo, Daniel, Maymó-Masip, Elsa, Rodríguez, M. Mar, Fradera, Rosa, de la Rosa, Juan Vladimir, Jorba, Rosa, Megia, Ana, Zorzano, Antonio, Medina-Gómez, Gema, Serena, Carolina, Castrillo, Antonio, Vendrell, Joan, Fernández-Veledo, Sonia
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2019; Nature Publishing Group
• Subjects: 631/250; 692/420; 692/699; Activation; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - immunology; Adipose Tissue - metabolism; Animals; Anti-inflammatory agents; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell activation; Cell receptors; Cells, Cultured; Cytokines; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Development and progression; Diet; Gene Expression Profiling - methods; Genotype & phenotype; Glucose; Health aspects; Homeostasis; Humans; Immunology; Infectious Diseases; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interleukin 4; Interleukins; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Metabolic response; Metabolism; Metabolites; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Obesity - genetics; Obesity - immunology; Obesity - metabolism; Phenotypes; Physiological aspects; 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 Cells; Type 2 diabetes
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-019-0372-7

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.