2. Academic Validation
  3. Prostaglandin F2α Facilitates Hepatic Glucose Production Through CaMKIIγ/p38/FOXO1 Signaling Pathway in Fasting and Obesity

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

  • Diabetes. 2018 Sep;67(9):1748-1760. doi: 10.2337/db17-1521.
Yuanyang Wang 1,  Shuai Yan 2,  Bing Xiao 2 3,  Shengkai Zuo 2,  Qianqian Zhang 2,  Guilin Chen 1,  Yu Yu 2 4,  Di Chen 2 5,  Qian Liu 1,  Yi Liu 2,  Yujun Shen 6,  Ying Yu 6 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, People's Republic of China.
  • 2 Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
  • 3 State Key Laboratory for Medical Genomics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
  • 4 Department of Pediatric Cardiology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
  • 5 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI.
  • 6 Department of Pharmacology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, People's Republic of China yuying@sibs.ac.cn yuying@tmu.edu.cn yujun_shen@tmu.edu.cn.
PMID: 29773555 DOI: 10.2337/db17-1521
Abstract

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.

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  • HY-15465
    99.19%, CaMK II Inhibitor‎