Lack of adipocyte purinergic P2Y₆ receptor greatly improves whole body glucose homeostasis

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.