期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：48
页码：30763-30774
DOI：10.1073/pnas.2006578117
出版社：The National Academy of Sciences of the United States of America
摘要：Uridine diphosphate (UDP)-activated purinergic receptor P2Y 6 (P2Y 6 R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y 6 R’s roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising finding that adipocyte-specific deletion of P2Y 6 R 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, P2Y 6 R deletion in skeletal muscle reduced glucose uptake, resulting in impaired glucose homeostasis. Interestingly, whole body P2Y 6 R knockout mice showed metabolic improvements similar to those observed with mice lacking P2Y 6 R only in adipocytes. Our findings provide compelling evidence that P2Y 6 R antagonists may prove useful for the treatment of obesity and type 2 diabetes.
