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Nat Immunol. 2019 May;20(5):581-592. doi: 10.1038/s41590-019-0372-7. Epub 2019 Apr 8.

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

Author information

1
Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.
2
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
3
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
4
Departamento de Ciencias Básicas de la Salud, Área de Bioquímica y Biología Molecular, Universidad Rey Juan Carlos, Madrid, Spain.
5
General and Digestive Surgery Service, Hospital St. Pau i Sta Tecla, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.
6
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
7
Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitaria (IUBIS), Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.
8
General and Digestive Surgery Service, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.
9
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain.
10
Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain. jvo@comt.es.
11
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. jvo@comt.es.
12
Universitat Rovira i Virgili, Tarragona, Spain. jvo@comt.es.
13
Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain. sonia.fernandezveledo@gmail.com.
14
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. sonia.fernandezveledo@gmail.com.

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.

PMID:
30962591
DOI:
10.1038/s41590-019-0372-7
[Indexed for MEDLINE]

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