Prostaglandin F2α Facilitates Hepatic Glucose Production Through CaMKIIγ/p38/FOXO1 Signaling Pathway in Fasting and Obesity

• DOI: 10.2337/db17-1521
• Publication Date: 2018-05-17T14:00:11Z
• Authors: Yuanyang Wang; Shuai Yan; Bing Xiao; Shengkai Zuo; Qianqian Zhang; Guilin Chen; Yu Yu; Di Chen; Qian Liu; Yi Liu; Yujun Shen; Ying Yu
• Keywords: 0303 health sciences; Forkhead Box Protein O1; Active Transport, Cell Nucleus; Gluconeogenesis; Mice, Obese; Mice, Transgenic; Fasting; Diet, High-Fat; Dinoprost; Mice, Inbred C57BL; 03 medical and health sciences; Gene Expression Regulation; Liver; Animals; Humans; RNA Interference; Obesity; Insulin Resistance; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Protein Kinase Inhibitors; Cells, Cultured; Crosses, Genetic

Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating levels of prostaglandin (PG) F2α are also markedly elevated in diabetes; however, whether and how PGF2α regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF2α 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 Ca2+ release, which activated Ca2+/calmodulin-activated protein kinase IIγ (CaMKIIγ) to increase FOXO1 phosphorylation and subsequently accelerate its nuclear translocation. Blockage of p38 disrupted CaMKIIγ-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 CaMKIIγ/p38/FOXO1 signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes.