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SUCNR1-mediated Chemotaxis Of Macrophages Aggravates Obesity-induced Inflammation And Diabetes

J. V. van Diepen, J. Robben, G. Hooiveld, Claudia Carmone, M. Alsady, Lily Boutens, Melissa Bekkenkamp‐Grovenstein, A. Hijmans, U. Engelke, R. Wevers, M. Netea, C. Tack, R. Stienstra, P. Deen
Published 2017 · Biology, Medicine

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Aims/hypothesisObesity 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.MethodsSuccinate 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.ResultsWe 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).Conclusions/interpretationOur 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.Data availabilityThe 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.
This paper references
10.1016/s0021-9258(19)74276-8
Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates.
R. Feinstein (1993)
10.1073/PNAS.97.6.2826
Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates.
J. Weinberg (2000)
10.1038/nature02488
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors
W. He (2004)
10.1172/JCI29881
Obesity induces a phenotypic switch in adipose tissue macrophage polarization.
C. Lumeng (2007)
10.1182/BLOOD-2006-07-036269
Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins.
I. Macaulay (2007)
10.1016/J.AMJHYPER.2007.05.010
Circulating succinate is elevated in rodent models of hypertension and metabolic disease.
N. Sadagopan (2007)
10.1074/jbc.M710314200
Peroxisome Proliferator-activated Receptor γ Activation Promotes Infiltration of Alternatively Activated Macrophages into Adipose Tissue*
R. Stienstra (2008)
10.1172/JCI33293
Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney.
I. Toma (2008)
10.1016/j.cell.2008.08.040
Anatomical Profiling of G Protein-Coupled Receptor Expression
J. Regard (2008)
10.1038/ni.1657
Triggering the succinate receptor GPR91 on dendritic cells enhances immunity
T. Rubic (2008)
10.1097/ALN.0b013e3181799d45
Obesity-induced Insulin Resistance and Hyperglycemia: Etiologic Factors and Molecular Mechanisms
J. Martyn (2008)
10.1038/ijo.2008.229
Emerging role of adipose tissue hypoxia in obesity and insulin resistance
J. Ye (2009)
10.1074/jbc.M109.074252
Adipocyte Apoptosis, a Link between Obesity, Insulin Resistance, and Hepatic Steatosis*
N. Alkhouri (2009)
10.1038/ki.2010.333
High glucose and renin release: the role of succinate and GPR91.
J. Peti-Peterdi (2010)
10.1172/JCI45887
Adipose tissue remodeling and obesity.
K. Sun (2011)
10.1038/nm.2627
The cellular and signaling networks linking the immune system and metabolism in disease
O. Osborn (2012)
10.3389/fendo.2012.00022
The Succinate Receptor as a Novel Therapeutic Target for Oxidative and Metabolic Stress-Related Conditions
A. Ariza (2012)
10.1007/s00125-012-2648-4
Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice
B. M. Carvalho (2012)
10.1038/nature11986
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
G. Tannahill (2013)
10.1182/blood-2012-06-436212
Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences.
F. Martinez (2013)
10.18632/AGING.100563
Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions
Sandra Favret (2013)
Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha
GM Tannahill (2013)
10.1038/ncomms5711
IL-37 protects against obesity-induced inflammation and insulin resistance.
D. Ballak (2014)
10.2337/dc13-1205
Diabetes-Related Distress, Insulin Dose, and Age Contribute to Insulin-Associated Weight Gain in Patients With Type 2 Diabetes: Results of a Prospective Study
H. Jansen (2014)
10.2337/db14-0346
Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity
K. McCreath (2014)
10.1152/ajpendo.00271.2013
Metabolic remodeling of white adipose tissue in obesity.
Timothy D Cummins (2014)
10.1152/ajpendo.00430.2013
Interleukin-1β mediates macrophage-induced impairment of insulin signaling in human primary adipocytes
D. Gao (2014)
10.1371/journal.pone.0145342
Novel Markers to Delineate Murine M1 and M2 Macrophages
K. Jablonski (2015)
10.1084/jem.20160061
GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis
A. Littlewood-Evans (2016)



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10.1007/s11154-021-09667-9
Metabolic responses of light and taste receptors – unexpected actions of GPCRs in adipocytes
Onyinye Nuella Ekechukwu (2021)
10.3390/nu13051474
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Shaofeng Huo (2021)
10.1016/j.jacbts.2021.05.008
Cardio-Oncology
Anja Karlstaedt (2021)
10.1016/j.tem.2020.12.001
Role of Macrophages in the Endocrine System
A. Rehman (2021)
10.3389/fimmu.2021.661241
Immunometabolism: Towards a Better Understanding the Mechanism of Parasitic Infection and Immunity
Jing-yue Chen (2021)
10.1007/978-3-030-56319-6
The Role of Toll-Like Receptor 4 in Infectious and Non Infectious Inflammation
M. Parnham (2021)
10.3390/IMMUNO1010001
Reprogramming of Central Carbon Metabolism in Myeloid Cells upon Innate Immune Receptor Stimulation
L. Perrin-Cocon (2021)
10.1016/j.celrep.2021.109246
Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling.
Mette Trauelsen (2021)
10.3389/fimmu.2021.635738
Cellular Metabolites Regulate Central Nucleic Acid Sensing Pathways
Julia Blay-Cadanet (2021)
10.3390/life11010069
Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses
Inseo Choi (2021)
10.1186/s12933-021-01333-3
Elevated plasma succinate levels are linked to higher cardiovascular disease risk factors in young adults
Francisco J. Osuna-Prieto (2021)
10.3390/ijms222112048
SUCNR1 Is Expressed in Human Placenta and Mediates Angiogenesis: Significance in Gestational Diabetes
(2021)
10.3390/brainsci11030325
Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis
F. Shakova (2021)
10.1007/978-3-030-86684-6_4
Metabolic Pathways in Immune Cells Commitment and Fate
Renan Willian Alves (2021)
10.1155/2021/9980877
Remodeling of Macrophages in White Adipose Tissue under the Conditions of Obesity as well as Lipolysis
Xiaohui Tong (2021)
10.1038/s42255-021-00389-5
UCP1 governs liver extracellular succinate and inflammatory pathogenesis.
E. Mills (2021)
10.3389/fimmu.2021.705920
Metabolic Control of Smoldering Neuroinflammation
L. Peruzzotti-Jametti (2021)
10.17816/DV62216
Microneedling in the threatment of post-acne symptom complex
Aleksandr S. Bykanov (2021)
10.1111/febs.15715
More than just protein building blocks: how amino acids and related metabolic pathways fuel macrophage polarization
M. Kieler (2021)
10.3389/fimmu.2021.702835
Innate Immune System Orchestrates Metabolic Homeostasis and Dysfunction in Visceral Adipose Tissue During Obesity
Y. Zhen (2021)
10.1186/s12944-020-01342-3
A review on the biology and properties of adipose tissue macrophages involved in adipose tissue physiological and pathophysiological processes
Yunjia Li (2020)
10.1007/978-3-030-56319-6_11
Metabolic Reprogramming of Myeloid Cells Upon TLR4 Stimulation
L. Perrin-Cocon (2020)
10.1093/cvr/cvaa148
Mechanism of succinate efflux upon reperfusion of the ischaemic heart
H. Prag (2020)
10.1016/j.ceb.2019.12.005
Structural basis for GPCR signaling by small polar versus large lipid metabolites-discovery of non-metabolite ligands.
Michael Lückmann (2020)
10.3389/fmolb.2020.00150
Association Between Succinate Receptor SUCNR1 Expression and Immune Infiltrates in Ovarian Cancer
Jiawen Zhang (2020)
10.2337/dc20-0460
Impaired Succinate Response to a Mixed Meal in Obesity and Type 2 Diabetes Is Normalized After Metabolic Surgery
B. Astiarraga (2020)
10.20944/preprints202006.0011.v1
High Mobility Group Box 1 and Dickkopf-Related Protein 1 as New Biomarkers of Type 2 Diabetes Mellitus: Associations with Increased Glucose Toxicity and Atherogenicity and Lower β Cell Function
H. Al-Hakeim (2020)
10.3390/metabo10090372
Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages
Karl J Harber (2020)
10.1177/2048004019900748
Monocyte-mediated inflammation and cardiovascular risk factors in type 2 diabetes mellitus: A systematic review and meta-analysis of pre-clinical and clinical studies
Kabelo Mokgalaboni (2020)
10.1111/ijpo.12711
A combination of circulating chemokines as biomarkers of obesity‐induced insulin resistance at puberty
P. Rivera (2020)
10.1016/j.molcel.2020.04.002
Cytokine-like Roles for Metabolites in Immunity.
Z. Zasłona (2020)
10.1016/j.pharmthera.2020.107521
Pharmacological targets of metabolism in disease: Opportunities from macrophages.
A. Castegna (2020)
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