Abstract
Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor α (PPARα) 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 PPARα-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. PPARα 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 α–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.
Footnotes
- Received September 13, 2019.
- Accepted January 7, 2020.
This study was supported by grants from the National Natural Sciences Foundation of China (81973306, 81872866, and 81601227), the Fundamental Research Funds for the Central Universities (20720180042), the Health Science Research Personnel Training Program of Fujian Province (2018-CXB-30), and the Natural Science Foundation of Fujian, China (2016J01415 and 2016D019).
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- Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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