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Purinergic receptor Y2 (P2Y2)- dependent VCAM-1 expression promotes immune cell infiltration in metabolic syndrome

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Abstract

Sterile inflammation of visceral fat, provoked by dying adipocytes, links the metabolic syndrome to cardiovascular disease. Danger-associated molecular patterns, such as adenosine triphosphate (ATP), are released by activated or dying cells and orchestrate leukocyte infiltration and inflammation via the purinergic receptor P2Y2. The gene expression of ATP receptor P2Y2 did not change in several tissues in the course of obesity, but was increased within epididymal fat. Adipose tissue from P2Y −/−2 mice consuming high-fat diet (HFD) contained less crown-like structures with a reduced frequency of adipose tissue macrophages (ATMs). This was likely due to decreased leukocyte migration because of missing VCAM-1 exposition on P2Y2 deficient hypertrophic adipose tissue endothelial cells. Accordingly, P2Y −/−2 mice showed blunted traits of the metabolic syndrome: they gained less weight compared to P2Y +/+2 controls, while intake of food and movement behaviour remained unchanged. Liver and adipose tissue were smaller in P2Y −/−2 animals. Insulin tolerance testing (ITT) performed in obese P2Y −/−2 mice revealed a better insulin sensitivity as well as lower plasma C-peptide and cholesterol levels. We demonstrate that interfering with somatic P2Y2 signalling prevents excessive immune cell deposition in diet-induced obesity (DIO), both attenuating adipose tissue inflammation and ameliorating the metabolic phenotype. Thus, blocking the P2Y2 cascade may be a promising strategy to limit metabolic disease and its sequelae.

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Funding

This work was supported by a research grant of the German Research Foundation to Peter Stachon and Andreas Zirlik (DFG STA 1446/2-1 and ZI 743/7-1). Philipp Albrecht was supported by a research grant of the German Cardiac Society (DGK). Sunaina von Garlen was supported by a research grant of German Society of Internal Medicine (DGIM).

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Author notes

  1. Julian Merz and Philipp Albrecht have contributed equally to this work.

    Andreas Zirlik and Peter Stachon have contributed equally as senior authors to this work.

Authors and Affiliations

  1. Department of Cardiology and Angiology I, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany

    Julian Merz, Philipp Albrecht, Sunaina von Garlen, Ibrahim Ahmed, Daniel Dimanski, Dennis Wolf, Ingo Hilgendorf, Carmen Härdtner, Katja Grotius, Florian Willecke, Timo Heidt, Heiko Bugger, Natalie Hoppe, Constantin von zur Mühlen, Christoph Bode, Andreas Zirlik & Peter Stachon

  2. Faculty of Biology, University of Freiburg, Freiburg, Germany

    Julian Merz

  3. Center for Cardiovascular Research, Institute of Pharmacology, Charité Universitaetsmedizin Berlin, Berlin, Germany

    Ulrich Kintscher

  4. Department of Pneumology, Medical University of Vienna, Vienna, Austria

    Marco Idzko

  5. Department of Cardiology, Medical University of Graz, Graz, Austria

    Andreas Zirlik

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  1. Julian Merz
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Correspondence to Peter Stachon.

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Merz, J., Albrecht, P., von Garlen, S. et al. Purinergic receptor Y2 (P2Y2)- dependent VCAM-1 expression promotes immune cell infiltration in metabolic syndrome. Basic Res Cardiol 113, 45 (2018). https://doi.org/10.1007/s00395-018-0702-1

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