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 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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