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Lack of adipocyte purinergic P2Y6 receptor greatly improves whole body glucose homeostasis [Physiology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-12-01 , DOI: 10.1073/pnas.2006578117
Shanu Jain 1 , Sai P Pydi 2 , Kiran S Toti 1 , Bernard Robaye 3 , Marco Idzko 4, 5 , Oksana Gavrilova 6 , Jürgen Wess 2 , Kenneth A Jacobson 7
Affiliation  

Uridine diphosphate (UDP)-activated purinergic receptor P2Y6 (P2Y6R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y6R’s roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising finding that adipocyte-specific deletion of P2Y6R protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling and enhanced expression and activity of PPARα affecting downstream PGC1α levels leading to beiging of white fat. In contrast, P2Y6R deletion in skeletal muscle reduced glucose uptake, resulting in impaired glucose homeostasis. Interestingly, whole body P2Y6R knockout mice showed metabolic improvements similar to those observed with mice lacking P2Y6R only in adipocytes. Our findings provide compelling evidence that P2Y6R antagonists may prove useful for the treatment of obesity and type 2 diabetes.



中文翻译:

缺乏脂肪细胞嘌呤能 P2Y6 受体极大地改善了全身葡萄糖稳态 [生理学]

尿苷二磷酸 (UDP) 激活的嘌呤能受体 P2Y 6 (P2Y 6 R) 在通过中枢机制控制能量平衡中起着至关重要的作用。然而,P2Y 6 R 在调节能量和葡萄糖稳态的外周组织中的作用仍未得到探索。在这里,我们报告了令人惊讶的发现,即 P2Y 6 R的脂肪细胞特异性缺失可保护小鼠免受饮食诱导的肥胖,改善葡萄糖耐量和胰岛素敏感性,同时减少全身炎症。这些变化与 JNK 信号传导减少和 PPARα 表达和活性增强有关,影响下游 PGC1α 水平,导致白色脂肪呈米色。相比之下,P2Y 6骨骼肌中的 R 缺失降低了葡萄糖摄取,导致葡萄糖稳态受损。有趣的是,全身 P2Y 6 R 敲除小鼠的代谢改善与仅在脂肪细胞中缺乏 P2Y 6 R 的小鼠所观察到的相似。我们的研究结果提供了令人信服的证据,证明 P2Y 6 R 拮抗剂可能对治疗肥胖症和 2 型糖尿病有用。

更新日期:2020-12-02
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