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SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.

ABSTRACT: AIMS/HYPOTHESIS: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. METHODS: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. RESULTS: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). CONCLUSIONS/INTERPRETATION: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. DATA AVAILABILITY: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 .

SUBMITTER: van Diepen JA

PROVIDER: S-EPMC5487589 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.

van Diepen Janna A JA Robben Joris H JH Hooiveld Guido J GJ Carmone Claudia C Alsady Mohammad M Boutens Lily L Bekkenkamp-Grovenstein Melissa M Hijmans Anneke A Engelke Udo F H UFH Wevers Ron A RA Netea Mihai G MG Tack Cees J CJ Stienstra Rinke R Deen Peter M T PMT

Diabetologia 20170405 7

<h4>Aims/hypothesis</h4>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.<h4>Metho ...[more]

PMID: 28382382

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SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.

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SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.

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