SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes
Open accessAbstract
Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1 −/− and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1 −/− mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1 −/− mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (−59%; p < 0.05). Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes. The dataset generated and analysed during the current study is available in GEO with the accession number GSE64104, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104 .
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The present study revealed novel effective and safe pharmacological modulators of PGC-1α, which determines increases in cellular energy production, neuron functionality, and viability.
“The present study revealed novel effective and safe pharmacological modulators of the transcription coactivator PGC-1α, which determines increases in cellular energy production, neuron functionality, and viability [2,5,17,80].”
From Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis (2021) · cites this paper as [80]
The Introduction and Results discuss succinate, SUCNR1, macrophage migration, and glucose tolerance, not PGC-1α modulators. Searches for PGC-1α, pharmacological modulators, and neuronal viability found no passage supporting the attributed claim; the copy is not marked as truncated. (LLM, conf=0.77)
Experimental — accuracy not yet measuredIn limited oxygen, HIF-1α degradation is prevented, allowing translocation to the nucleus, dimerization with HIF-1β and binding of target genes.
“This degradation is prevented in conditions of limited oxygen, allowing for HIF-1α translocation to the nucleus, dimerization with HIF-1β and binding of target genes13.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [13]
BMDMs activated by LPS and pre-treated with dimethyl itaconate exhibit potent inhibition of pro-inflammatory mediators including NO, ROS and cytokines IL-6, IL-12p70 and IL-1β.
“Importantly, Lampropoulou and colleagues (2016) first demonstrated that bone-marrow derived macrophages (BMDMs) activated by LPS and pre-treated with a cell permeable methyl ester derivative of itaconate, dimethyl itaconate (DI), exhibited potent inhibition of pro-inflammatory mediators including nitic oxide (NO), ROS and the cytokines IL-6, IL-12p70 and IL-1β13,50.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [13]
Fumarate accumulates in LPS-activated macrophages.
“Outside of trained immunity, fumarate has previously been reported to accumulate in LPS-activated macrophages1,13.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [13]
Succinate production is enhanced during inflammation, acting as a signal from mitochondria to cytosol to activate pro-inflammatory gene expression and generating ROS as a pro-inflammatory redox signal.
“The production of succinate is also enhanced during inflammation13, acting as a signal from mitochondria to the cytosol to activate pro-inflammatory gene expression while also generating ROS as a further pro-inflammatory redox signal28.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [13]
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“The present study revealed novel effective and safe pharmacological modulators of the transcription coactivator PGC-1α, which determines increases in cellular energy production, neuron functionality, and viability [2,5,17,80].”
Background
- Authors
- van Diepen, J. A., Robben, J. H., Hooiveld, G. J., Carmone, C., Alsady, M., Boutens, L., Bekkenkamp-Grovenstein, M., Hijmans, A., Engelke, U. F. H., Wevers, R. A., Netea, M. G., Tack, C. J., Stienstra, R., & Deen, P. M. T.
- Affiliations
- Radboud University Medical Center (NL)
- Wageningen University & Research (NL)
- Corresponding author
- Deen, Peter M. T.
- ORCID
- Venue
- Diabetologia
- Published
- 2017-04-05
- Volume
- 60
- Issue
- 7
- Pages
- 1304-1313
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC5487589
- OpenAlex
- W2604899386
- Cited by
- 187
- References
- 28
- Citations by year
- 2026: 23 · 2025: 20 · 2024: 20 · 2023: 18 · 2022: 25 · 2021: 32 · 2020: 22 · 2019: 10 · 2018: 14 · 2017: 2
- FWCI
- 10.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion, cc-by)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Nierstichting (KJPB 09.012)
- European Foundation for the Study of Diabetes (EFSD/Lilly Fellowship 2012 to JHR)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (91616083)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- SUCNR1, succinate receptor, macrophage chemotaxis, obesity, adipose tissue inflammation, type 2 diabetes, succinic acid, TCA cycle, hypoxia, hyperglycemia, glucose tolerance, crown-like structures, high-fat diet, adipocyte apoptosis, metabolic signaling
- MeSH terms
- Adipose Tissue, Adult, Aged, Animals, Hypoxia, Blood Glucose, Body Weight, Cell Movement, Chemotaxis, Citric Acid Cycle, Diabetes Mellitus, Diabetes Mellitus, Type 2, Glucose Tolerance Test, Humans, Hyperglycemia, Inflammation, Insulin Resistance, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Obesity, Signal Transduction, Adipocytes, Diet, Fat-Restricted, Receptors, G-Protein-Coupled, Mice, Diet, High-Fat
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