1643-P: P2Y₁₄ Receptor Regulates Whole-Body Glucose Homeostasis in High Fat Diet-Induced Obese and Diabetic Mice

Diverse G protein-coupled receptors (GPCRs) are expressed in different metabolic tissues and are involved in the regulation of whole-body glucose and energy homeostasis. Dysregulation of glucose homeostasis contributes to hyperglycemia in obesity and type 2 diabetes (T2D). Thus, GPCRs have emerged as important therapeutic targets for anti-obesity and anti-diabetic candidate. P2Y₁₄ receptor (P2Y₁₄R) is a G_i-coupled purinergic receptor stimulated by endogenous UDP-glucose and functionally expressed in adipose tissue involved in glucose and lipid homeostasis. P2Y₁₄R plays a crucial role in adipocyte metabolism, and its selective ablation in adipocytes improves metabolic phenotypes. However, the role of P2Y₁₄R signaling in hepatic glucose production (HGP) and insulin secretion in obese mice has remained elusive. Here, we investigated this receptor in glucose metabolism using selective P2Y₁₄R small molecule modulators. The P2Y₁₄R mRNA level is upregulated in mouse hepatocytes and islets isolated from high fat diet-induced obese mice compared to lean control mice. A potent synthetic P2Y₁₄R agonist (MRS2905) was administered to lean and obese mice to selectively activate P2Y₁₄R. Surprisingly, acute activation impaired glucose homeostasis by enhancing HGP and suppressing insulin secretion in mice consuming high fat diet as well as lean mice. In contrast, P2Y₁₄R antagonist mono-prodrug (MRS 4779) improved HGP and protected mice from metabolic deficits. Overall, our evidence suggests that P2Y₁₄R activation triggers defects in glucose metabolism whereas antagonist prodrugs can contribute to improve whole-body glucose homeostasis in obese mice. Hence, P2Y₁₄R antagonists and their prodrugs might have potential for use in anti-diabetic therapy.