Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892.
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30763-30774. doi: 10.1073/pnas.2006578117. Epub 2020 Nov 16.
Uridine diphosphate (UDP)-activated purinergic receptor P2Y (P2YR) plays a crucial role in controlling energy balance through central mechanisms. However, P2YR's roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising finding that adipocyte-specific deletion of P2YR 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, P2YR deletion in skeletal muscle reduced glucose uptake, resulting in impaired glucose homeostasis. Interestingly, whole body P2YR knockout mice showed metabolic improvements similar to those observed with mice lacking P2YR only in adipocytes. Our findings provide compelling evidence that P2YR antagonists may prove useful for the treatment of obesity and type 2 diabetes.
尿苷二磷酸（UDP）激活的嘌呤能受体 P2Y（P2YR）通过中枢机制在控制能量平衡方面发挥着至关重要的作用。然而，P2YR 在调节能量和葡萄糖稳态的外周组织中的作用仍未被探索。在这里，我们报告了一个令人惊讶的发现，即脂肪细胞特异性敲除 P2YR 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，并降低全身炎症。这些变化与 JNK 信号的减少以及 PPARα 的表达和活性增强有关，这影响了下游 PGC1α 水平，导致白色脂肪的米色化。相比之下，骨骼肌中 P2YR 的缺失会减少葡萄糖摄取，导致葡萄糖稳态受损。有趣的是，全身 P2YR 敲除小鼠表现出与仅在脂肪细胞中缺乏 P2YR 的小鼠相似的代谢改善。我们的研究结果提供了令人信服的证据，表明 P2YR 拮抗剂可能有助于肥胖和 2 型糖尿病的治疗。
