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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose 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 Cells


  • Cytokines
  • GPR91 protein, mouse
  • Receptors, G-Protein-Coupled
  • Succinic Acid