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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 Gi-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. Disclosure A. Pramanik: None. K.A. Jacobson: None. Funding National Institutes of Health (ZIADK031126)
PRAMANIK et al. (Fri,) studied this question.