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

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

doi:10.1007/s00395-018-0702-1

Cited by 47 publications

(29 citation statements)

References 31 publications

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“…In the current study, we show that KO mice are significantly resistant to high-fat diet (HFD) induced weight gain or obesity. These findings are in agreement with those of Merz et al (49) who studied the effects of a high-fat/high sugar diet fed for 20 weeks to male P2Y 2 whole-body KO mice on a different background strain (C57Bl6). Thus, the finding of relatively "lean phenotype" appears robust and independent of background strain, and dietary sugar.…”

Section: Discussionsupporting

confidence: 93%

P2Y2 Receptor Promotes High-Fat Diet-Induced Obesity

et al. 2020

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P2Y 2 , a G protein-coupled receptor (R), is expressed in all organs involved in the development of obesity and insulin resistance. To explore the role of it in diet-induced obesity, we fed male P2Y 2-R whole body knockout (KO) and wild type (WT) mice (B6D2 genetic background) with regular diet (CNT; 10% calories as fat) or high-fat diet (HFD; 60% calories as fat) with free access to food and water for 16 weeks, and euthanized them. Adjusted for body weights (BW), KO mice consumed modestly, but significantly more HFD vs. WT mice, and excreted well-formed feces with no taint of fat or oil. Starting from the 2nd week, HFD-WT mice displayed significantly higher BW with terminal mean difference of 22% vs. HFD-KO mice. Terminal weights of white adipose tissue (WAT) were significantly lower in the HFD-KO vs. HFD-WT mice. The expression of P2Y 2-R mRNA in WAT was increased by 2-fold in HFD-fed WT mice. Serum insulin, leptin and adiponectin levels were significantly elevated in the HFD-WT mice, but not in the HFD-KO mice. When induced in vitro, preadipocytes derived from KO mice fed regular diet did not differentiate and mature as robustly as those from the WT mice, as assessed by cellular expansion and accumulation of lipid droplets. Blockade of P2Y 2-R by AR-C118925 in preadipocytes derived from WT mice prevented differentiation and maturation. Under basal conditions, KO mice had significantly higher serum triglycerides and showed slightly impaired lipid tolerance as compared to the WT mice. HFD-fed KO mice had significantly better glucose tolerance (GTT) as compared to HFD-fed WT mice. Whole body insulin sensitivity and mRNA expression of insulin receptor, IRS-1 and GLUT4 in WAT was significantly higher in HFD-fed KO mice vs. HFD-fed WT mice. On the contrary, the expression of pro-inflammatory molecules MCP-1, CCR2, CD68, and F4/80 were significantly higher in the WAT of HFD-fed WT vs. HFD-fed KO mice. These data suggest that P2Y 2-R plays a significant role in the development of diet-induced obesity by promoting adipogenesis and inflammation, and altering the production of adipokines and lipids and their metabolism in adipose tissue, and thereby facilitates HFD-induced insulin resistance.

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Section: Discussionsupporting

confidence: 93%

P2Y2 Receptor Promotes High-Fat Diet-Induced Obesity

et al. 2020

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“…These are the mitochondria‐related caspase‐9 apoptosis axis, the ER‐mediated caspase‐12 death pathway and the Fas‐dependent necrosis cascade. In the present study, mitochondrial apoptosis was determined in response to resveratrol treatment . Firstly, capsase‐9 activity was determined via ELISA.…”

Section: Resultsmentioning

confidence: 98%

“…In the present study, mitochondrial apoptosis was determined in response to resveratrol treatment. 55,56 Firstly, capsase-9 activity was determined via ELISA. As shown in Figure 2A, compared to the control group, HR injury elevated the caspase-9 activity, implicating caspase-9 at the stage of reperfusion injury.…”

Section: Resveratrol Inhibits Mitochondrial Apoptosis In N2a Cellmentioning

confidence: 99%

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Gao

Wang

et al. 2019

Int J Experimental Path

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Summary The pathogenesis of cerebral ischaemia reperfusion injury (IRI) has not been fully described. Accordingly, there is little effective drug available for the treatment of cerebral IRI. The aim of our study was to explore the exact role played by Mfn1‐mediated mitochondrial protection in cerebral IRI and evaluate the beneficial action of resveratrol on reperfused brain. Our study demonstrated that hypoxia‐reoxygenation (HR) injury caused N2a cell apoptosis and this process was highly affected by mitochondrial dysfunction. Decreased mitochondrial membrane potential, increased mitochondrial oxidative stress, and an activated mitochondrial apoptosis pathway were noted in HR‐treated N2a cells. Interestingly, resveratrol treatment could attenuate N2a cell apoptosis via sustaining mitochondrial homeostasis. Further, we found that resveratrol modulated mitochondrial performance via activating the Mfn1‐related mitochondrial protective system. Knockdown of Mfn1 could abolish the beneficial effects of resveratrol on HR‐treated N2a cells. Besides, we also report that resveratrol regulated Mfn1 expression via the AMPK pathway; inhibition of AMPK pathway also neutralized the anti‐apoptotic effect of resveratrol on N2a cells in the setting of cerebral IRI. Taken together our results show that mitochondrial damage is closely associated with the progression of cerebral IRI. In addition we also demonstrate the protective action played by resveratrol on reperfused brain and show that this effect is achieved via activating the AMPK‐Mfn1 pathway.

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“…Inhibition or deletion of P2Y 4 receptors increased adiponectin secretion in cardiac adipocytes and was cardioprotective (Lemaire et al, 2017). In P2Y 2 receptor knockout (KO) mice on high‐fat diet, there was decreased immune cell infiltration and inflammation of adipose tissue, as well as a lower fat and body weight (Merz et al, 2018). In addition, hepatic steatosis was improved, and animals were protected against insulin resistance and hypercholestoremia, all indicating that the P2Y 2 receptor is a promising target to combat the initial phases of metabolic syndrome.…”

Section: P2y Receptors In Endocrine and Exocrine Functionmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

179

184

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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

Cited by 47 publications

References 31 publications

P2Y2 Receptor Promotes High-Fat Diet-Induced Obesity

P2Y2 Receptor Promotes High-Fat Diet-Induced Obesity

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Update of P2Y receptor pharmacology: IUPHAR Review 27

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