Prostaglandin F2αFacilitates Hepatic Glucose Production Through CaMKIIγ/p38/FOXO1 Signaling Pathway in Fasting and Obesity
Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating levels of prostaglandin (PG) F 2a are also markedly elevated in diabetes; however, whether and how PGF 2a regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF 2a receptor (F-prostanoid receptor [FP]) was upregulated in the livers of mice upon fastingand diabetic stress. Hepatic deletion of the FP receptor
... receptor suppressed fasting-induced hepatic gluconeogenesis, whereas FP overexpression enhanced hepatic gluconeogenesis in mice. FP activation promoted the expression of gluconeogenic enzymes (PEPCK and glucose-6phosphatase) in hepatocytes in a FOXO1-dependent manner. Additionally, FP coupled with G q in hepatocytes to elicit Ca 2+ release, which activated Ca 2+ /calmodulinactivated protein kinase IIg (CaMKIIg) to increase FOXO1 phosphorylation and subsequently accelerate its nuclear translocation. Blockage of p38 disrupted CaMKIIginduced FOXO1 nuclear translocation and abrogated FPmediated hepatic gluconeogenesis in mice. Moreover, knockdown of hepatic FP receptor improved insulin sensitivity and glucose homeostasis in ob/ob mice. FP-mediated hepatic gluconeogenesis via the CaMKIIg/p38/FOXO1 signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes.