P2Y14 receptor agonist impairs, and antagonist improves whole-body glucose homeostasis and liver steatosis
- 1National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Abstract
Knockout of the UDP-glucose-activated P2Y14 receptor (P2Y14R) in adipocytes or whole-body has been reported to provide metabolic benefits in obese mice. We hypothesized that selective P2Y14R 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 P2Y14R agonist, UDP-like methylene-bridged MRS2905. Acute P2Y14R 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 P2Y14R knockout mice compared with wild-type control. In contrast, a potent P2Y14R 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 P2Y14R in hepatocytes of DIO mice. Here, we report that P2Y14R was upregulated in liver and hepatocytes from obese mice compared to lean mice. Overnight fasting also upregulated hepatic P2Y14R expression. P2Y14R deletion from hepatocytes in DIO mice improved fasting blood glucose level and lipid metabolism without improving glucose homeostasis. These results suggest a novel P2Y14R function in hepatic lipid metabolism, and P2Y14R antagonists may prove useful for the treatment of obesity and obesity-related metabolic disorders.
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BibTeX
@misc{pramanik2026p2y14,
title = {{P2Y14 receptor agonist impairs, and antagonist improves whole-body glucose homeostasis and liver steatosis}},
author = {A. Pramanik and S. Hariprasad Kurma and Z. Wen and H. Cai and P.-C. Violet and P. J. Walter and T. Demby and O. Gavrilova and S. Pittala and H. Sajiir and R. Umarova and A. Wing and Y. Rotman and J. Wess and K. A. Jacobson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748648},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748648v1},
note = {CC0},
}
RIS
TY - UNPB
TI - P2Y14 receptor agonist impairs, and antagonist improves whole-body glucose homeostasis and liver steatosis
AU - A. Pramanik
AU - S. Hariprasad Kurma
AU - Z. Wen
AU - H. Cai
AU - P.-C. Violet
AU - P. J. Walter
AU - T. Demby
AU - O. Gavrilova
AU - S. Pittala
AU - H. Sajiir
AU - R. Umarova
AU - A. Wing
AU - Y. Rotman
AU - J. Wess
AU - K. A. Jacobson
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748648
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748648v1
AB - Knockout of the UDP-glucose-activated P2Y14 receptor (P2Y14R) in adipocytes or whole-body has been reported to provide metabolic benefits in obese mice. We hypothesized that selective P2Y14R 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 P2Y14R agonist, UDP-like methylene-bridged MRS2905. Acute P2Y14R 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 P2Y14R knockout mice compared with wild-type control. In contrast, a potent P2Y14R 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 P2Y14R in hepatocytes of DIO mice. Here, we report that P2Y14R was upregulated in liver and hepatocytes from obese mice compared to lean mice. Overnight fasting also upregulated hepatic P2Y14R expression. P2Y14R deletion from hepatocytes in DIO mice improved fasting blood glucose level and lipid metabolism without improving glucose homeostasis. These results suggest a novel P2Y14R function in hepatic lipid metabolism, and P2Y14R antagonists may prove useful for the treatment of obesity and obesity-related metabolic disorders.
ER -