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

Identifier:  imarina:4899351

Handle: https://hdl.handle.net/20.500.11797/imarina4899351

Authors:  Keiran, Noelia; Ceperuelo-Mallafre, Victoria; Calvo, Enrique; Isabel Hernandez-Alvarez, Maria; Ejarque, Miriam; Nunez-Roa, Catalina; Horrillo, Daniel; Maymo-Masip, Elsa; Mar Rodriguez, M; Fradera, Rosa; Vladimir de la Rosa, Juan; Jorba, Rosa; Megia, Ana; Zorzano, Antonio; Medina-Gomez, Gema; Serena, Carolina; Castrillo, Antonio; Vendrell, Joan; Fernandez-Veledo, Sonia

Abstract:
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.