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

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 P2Y2 -/-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, P2Y2 -/-mice showed blunted traits of the metabolic syndrome: they gained less weight compared to P2Y2 +/+ controls, while intake of food and movement behaviour remained unchanged. Liver and adipose tissue were smaller in P2Y2 -/-animals. Insulin tolerance testing (ITT) performed in obese P2Y2 -/-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.