P2Y 14 receptor regulates adipocyte lipid mobilization and whole‐body glucose homeostasis

Abstract

The incidence and prevalence of obesity and type 2 diabetes (T2D) is rapidly increasing worldwide. Obesity is associated with chronically elevated plasma free fatty acid (FFA) levels, causing peripheral insulin resistance and T2D. Drugs that are able to regulate adipocyte lipolytic processes, improving insulin sensitivity and whole-body glucose homeostasis, have considerable therapeutic potential. Gi-coupled P2Y14 receptor (P2Y14R), activated by UDP-glucose is abundantly expressed in mouse and human adipocytes. P2Y14R activation in primary mouse adipocytes decreased cAMP levels and CL-316,243 (β3-adrenoceptor agonist) induced lipolysis. To investigate the physiological relevance of adipocyte P2Y14Rs in regulating lipid and glucose homeostasis in-vivo, we generated a mouse model lacking P2Y14R specifically in adipocytes. Lack of adipocyte P2Y14R increased lipolysis only in the fasting state, resulting in decreased body weight, improved glucose tolerance and insulin sensitivity. Accordingly, high fat diet increased, whereas fasting decreased P2Y14R expression in visceral white adipocytes. Mechanistic studies suggested that activation of P2Y14R reduced the activity of lipolytic enzymes including ATGL and HSL, thereby inhibiting lipolysis. Supporting these findings, administration of P2Y14R agonist in control mice decreased lipolysis. Coadministration of P2Y14R antagonist with the P2Y14R agonist rescued the decrease in lipolysis. In conclusion, we demonstrate that lack of adipocyte P2Y14R decreased diet-induced obesity by enhancing lipolysis in the fasting state, suggesting that P2Y14R antagonists may prove beneficial for the therapy of obesity and T2D.