Department of Cardiology and Angiology I, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Basic Res Cardiol. 2018 Oct 18;113(6):45. doi: 10.1007/s00395-018-0702-1.
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 P2Y. The gene expression of ATP receptor P2Y did not change in several tissues in the course of obesity, but was increased within epididymal fat. Adipose tissue from P2Y 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 P2Y deficient hypertrophic adipose tissue endothelial cells. Accordingly, P2Y mice showed blunted traits of the metabolic syndrome: they gained less weight compared to P2Y controls, while intake of food and movement behaviour remained unchanged. Liver and adipose tissue were smaller in P2Y animals. Insulin tolerance testing (ITT) performed in obese P2Y mice revealed a better insulin sensitivity as well as lower plasma C-peptide and cholesterol levels. We demonstrate that interfering with somatic P2Y signalling prevents excessive immune cell deposition in diet-induced obesity (DIO), both attenuating adipose tissue inflammation and ameliorating the metabolic phenotype. Thus, blocking the P2Y cascade may be a promising strategy to limit metabolic disease and its sequelae.
内脏脂肪的无菌性炎症是由死亡的脂肪细胞引发的，它将代谢综合征与心血管疾病联系起来。危险相关的分子模式，如三磷酸腺苷（ATP），是由激活或死亡的细胞释放的，并通过嘌呤能受体 P2Y 来协调白细胞浸润和炎症。在肥胖过程中，几种组织中的 ATP 受体 P2Y 的基因表达没有改变，但在附睾脂肪中增加。进食高脂肪饮食（HFD）的 P2Y 缺陷小鼠的脂肪组织中，冠层样结构较少，脂肪组织巨噬细胞（ATMs）的频率降低。这可能是由于 P2Y 缺陷的肥大脂肪组织内皮细胞中缺少 VCAM-1 暴露，导致白细胞迁移减少。因此，P2Y 缺陷小鼠表现出代谢综合征特征减弱：与 P2Y 对照组相比，它们体重增加较少，而食物摄入和运动行为保持不变。P2Y 动物的肝脏和脂肪组织较小。在肥胖的 P2Y 缺陷小鼠中进行的胰岛素耐量试验（ITT）显示出更好的胰岛素敏感性，以及更低的血浆 C 肽和胆固醇水平。我们证明，干扰体细胞 P2Y 信号可以防止饮食诱导的肥胖（DIO）中过度的免疫细胞沉积，既能减轻脂肪组织炎症，又能改善代谢表型。因此，阻断 P2Y 级联反应可能是限制代谢性疾病及其后果的一种有前途的策略。
