P2Y14 receptor agonist impairs, and antagonist improves whole-body glucose homeostasis and liver steatosis

Knockout of the UDP-glucose-activated P2Y ₁₄ receptor (P2Y ₁₄ R) in adipocytes or whole-body has been reported to provide metabolic benefits in obese mice. We hypothesized that selective P2Y ₁₄ R activation would lead to metabolic impairments, whereas pharmacological antagonism would improve metabolic deficits in diet-induced obese (DIO) mice. Here, we investigated the metabolic effects of a synthetic P2Y ₁₄ R agonist, UDP-like methylene-bridged MRS2905. Acute P2Y ₁₄ R activation with MRS2905 triggered a robust and prolonged hyperglycemic effect in lean and obese mice with impaired glucose homeostasis. Moreover, MRS2905 treatment of obese mice lowered fasting plasma insulin and increased glucagon levels, along with upregulation of liver JNK phosphorylation and the expression of rate-limiting gluconeogenic genes. The MRS2905-induced hyperglycemic effect was blunted in whole-body P2Y ₁₄ R knockout mice compared with wild-type control. In contrast, a potent P2Y ₁₄ R antagonist mono-ester prodrug (MRS4779) partially reversed the agonist-induced hyperglycemia and restored proper glucose homeostasis after acute treatment. Chronic MRS4779 administration in DIO mice reduced fat mass and improved various metabolic parameters including liver steatosis. Additionally, we examined the roles of P2Y ₁₄ R in hepatocytes of DIO mice. Here, we report that P2Y ₁₄ R was upregulated in liver and hepatocytes from obese mice compared to lean mice. Overnight fasting also upregulated hepatic P2Y ₁₄ R expression. P2Y ₁₄ R deletion from hepatocytes in DIO mice improved fasting blood glucose level and lipid metabolism without improving glucose homeostasis. These results suggest a novel P2Y ₁₄ R function in hepatic lipid metabolism, and P2Y ₁₄ R antagonists may prove useful for the treatment of obesity and obesity-related metabolic disorders.