title: SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.
abstract: 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 .
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.affiliation: Department of Physiology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Joris H
authors.initials: JH
authors.lastname: Robben
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Hooiveld
authors.affiliation: Department of Physiology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Carmone
authors.affiliation: Department of Physiology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alsady
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Lily
authors.initials: L
authors.lastname: Boutens
authors.affiliation: Department of Physiology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bekkenkamp-Grovenstein
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Hijmans
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Udo F H
authors.initials: UFH
authors.lastname: Engelke
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.affiliation: Department of Physiology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands. Peter.Deen@radboudumc.nl.
authors.forename: Peter M T
authors.initials: PMT
authors.lastname: Deen
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002465:Cell Movement; D002633:Chemotaxis; D002952:Citric Acid Cycle; D003920:Diabetes Mellitus / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D000860:Hypoxia; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; C531499:GPR91 protein, mouse; D043562:Receptors, G-Protein-Coupled; C557078:SUCNR1 protein, human
keywords: Adipose tissue; Chemotaxis; Glucose; Inflammation; Macrophage; Obesity; Succinate; TCA cycle