| First Author | Wang Y | Year | 2018 |
| Journal | Diabetes | Volume | 67 |
| Issue | 9 | Pages | 1748-1760 |
| PubMed ID | 29773555 | Mgi Jnum | J:264585 |
| Mgi Id | MGI:6196448 | Doi | 10.2337/db17-1521 |
| Citation | Wang Y, et al. (2018) Prostaglandin F2alpha Facilitates Hepatic Glucose Production Through CaMKIIgamma/p38/FOXO1 Signaling Pathway in Fasting and Obesity. Diabetes 67(9):1748-1760 |
| abstractText | Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating levels of prostaglandin (PG) F2alpha are also markedly elevated in diabetes; however, whether and how PGF2alpha regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF2alpha receptor (F-prostanoid receptor [FP]) was upregulated in the livers of mice upon fasting- and diabetic stress. Hepatic deletion of the FP 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-6-phosphatase) in hepatocytes in a FOXO1-dependent manner. Additionally, FP coupled with Gq in hepatocytes to elicit Ca(2+) release, which activated Ca(2+)/calmodulin-activated protein kinase IIgamma (CaMKIIgamma) to increase FOXO1 phosphorylation and subsequently accelerate its nuclear translocation. Blockage of p38 disrupted CaMKIIgamma-induced FOXO1 nuclear translocation and abrogated FP-mediated 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 CaMKIIgamma/p38/FOXO1 signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes. |
