P2Y2 Receptor Upregulation and Signaling during Adipogenesis and Inflammation: a New Mechanism in Insulin Resistance.

It has been known that obesity is associated with inflammation and insulin resistance and that adipose tissue contributes to insulin sensitivity and glucose homeostasis; however, the exact mechanism(s) of insulin resistance in adipose tissue remains incompletely understood. We hypothesized that inflammation promotes adipocyte P2Y2 receptor (P2Y2R) induction, leading to insulin resistance by inhibiting the insulin-AKT signaling pathway. Real-time RT-PCR revealed that the P2Y2R mRNA was significantly upregulated during human visceral pre-adipocytes differentiation into mature adipocytes in vitro. Stimulation of the mature adipocytes by TNFα further increased P2Y2R mRNA expression. Functional P2Y2R upregulation was confirmed by intracellular Ca mobilization assay in response to ATP or UTP stimulation in mature human visceral adipocytes. In addition, stimulation of the P2Y2R by ATP or UTP suppressed basal and insulin-induced phosphorylation of AKT in a dose-dependent manner in mature adipocytes. These effects were significantly diminished by AR-C118925, a selective P2Y2R antagonist, suggesting a negative role of P2Y2R in insulin receptor signaling. Furthermore, we found that activation of the P2Y2R inhibited insulin-induced glucose uptake in mature adipocytes. We concluded that the P2Y2R is upregulated during adipocyte differentiation and inflammation and that P2Y2R activation leads to insulin resistance by suppressing the AKT signaling pathway, highlighting P2Y2R being a potential new drug target to combat obesity and type-II diabetes.