PMID- 32024803 OWN - NLM STAT- MEDLINE DCOM- 20200908 LR - 20211204 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 373 IP - 1 DP - 2020 Apr TI - Oleoylethanolamide Increases Glycogen Synthesis and Inhibits Hepatic Gluconeogenesis via the LKB1/AMPK Pathway in Type 2 Diabetic Model. PG - 81-91 LID - 10.1124/jpet.119.262675 [doi] AB - Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor alpha (PPARalpha) agonist that acts on the peripheral control of energy metabolism. However, its therapeutic potential and related mechanisms in hepatic glucose metabolism under type 2 diabetes mellitus (T2DM) are not clear. Here, OEA treatment markedly improved glucose homeostasis in a PPARalpha-independent manner. OEA efficiently promoted glycogen synthesis and suppressed gluconeogenesis in mouse primary hepatocytes and liver tissue. OEA enhanced hepatic glycogen synthesis and inhibited gluconeogenesis via liver kinase B1 (LKB1)/5' AMP-activated protein kinase (AMPK) signaling pathways. PPARalpha was not involved in the roles of OEA in the LKB1/AMPK pathways. We found that OEA exerts its antidiabetic effect by increasing glycogenesis and decreasing gluconeogenesis via the LKB1/AMPK pathway. The ability of OEA to control hepatic LKB1/AMPK pathways may serve as a novel therapeutic approach for the treatment of T2DM. SIGNIFICANCE STATEMENT: Oleoylethanolamide (OEA) exerted a potent antihyperglycemic effect in a peroxisome proliferator-activated receptor alpha-independent manner. OEA played an antihyperglycemic role primarily via regulation of hepatic glycogen synthesis and gluconeogenesis. The main molecular mechanism of OEA in regulating liver glycometabolism is activating the liver kinase B1/5' AMP-activated protein kinase signaling pathways. CI - Copyright (c) 2020 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Ren, Tong AU - Ren T AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.). FAU - Ma, Ang AU - Ma A AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.). FAU - Zhuo, Rengong AU - Zhuo R AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.). FAU - Zhang, Huaying AU - Zhang H AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.). FAU - Peng, Lu AU - Peng L AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.). FAU - Jin, Xin AU - Jin X AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.). FAU - Yao, Enhui AU - Yao E AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.) enhuiyao@hotmail.com. FAU - Yang, Lichao AU - Yang L AUID- ORCID: 0000-0001-9945-2338 AD - Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.) yanglc116@xmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200205 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Blood Glucose) RN - 0 (Endocannabinoids) RN - 0 (Oleic Acids) RN - 1HI5J9N8E6 (oleoylethanolamide) RN - 9005-79-2 (Glycogen) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Stk11 protein, mouse) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - AMP-Activated Protein Kinases MH - Animals MH - Blood Glucose/drug effects/metabolism MH - Diabetes Mellitus, Experimental/blood/chemically induced/drug therapy MH - Diabetes Mellitus, Type 2/*blood/chemically induced/drug therapy MH - Endocannabinoids/*pharmacology/therapeutic use MH - Gluconeogenesis/drug effects/*physiology MH - Glycogen/*biosynthesis MH - Liver/drug effects/*metabolism MH - Male MH - Mice MH - Mice, 129 Strain MH - Mice, Knockout MH - Oleic Acids/*pharmacology/therapeutic use MH - Protein Kinases/metabolism MH - Protein Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects/physiology EDAT- 2020/02/07 06:00 MHDA- 2020/09/09 06:00 CRDT- 2020/02/07 06:00 PHST- 2019/09/13 00:00 [received] PHST- 2020/01/07 00:00 [accepted] PHST- 2020/02/07 06:00 [pubmed] PHST- 2020/09/09 06:00 [medline] PHST- 2020/02/07 06:00 [entrez] AID - jpet.119.262675 [pii] AID - 10.1124/jpet.119.262675 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2020 Apr;373(1):81-91. doi: 10.1124/jpet.119.262675. Epub 2020 Feb 5.