Journal
NPJ SCIENCE OF FOOD
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41538-021-00114-2
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Funding
- JSPS KAKENHI [JP18H02157, JP21H04863]
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This study aimed to develop a dipeptide with an agonistic effect on AdipoR1 in skeletal muscle, and found that Tyr-Pro was the most effective in promoting glucose uptake, likely through the activation of AMPK/Glut4 pathway in L6 myotubes. This dipeptide may directly interact with AdipoR1 as an agonist, as demonstrated by molecular dynamics simulations.
The aim of this study is to develop a dipeptide showing an adiponectin receptor 1 (AdipoR1) agonistic effect in skeletal muscle L6 myotubes. Based on the structure of the AdipoR1 agonist, AdipoRon, 15 synthetic dipeptides were targeted to promote glucose uptake in L6 myotubes. Tyr-Pro showed a significant increase in glucose uptake among the dipeptides, while other dipeptides, including Pro-Tyr, failed to exert this effect. Tyr-Pro induces glucose transporter 4 (Glut4) expression in the plasma membrane, along with adenosine monophosphate-activated protein kinase (AMPK) activation. In AdipoR1-knocked down cells, the promotion by Tyr-Pro was ameliorated, indicating that Tyr-Pro may directly interact with AdipoR1 as an agonist, followed by the activation of AMPK/Glut4 translocation in L6 myotubes. Molecular dynamics simulations revealed that a Tyr-Pro molecule was stably positioned in the two potential binding pockets (sites 1 and 2) of the seven-transmembrane receptor, AdipoR1, anchored in a virtual 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane. In conclusion, we demonstrated the antidiabetic function of the Tyr-Pro dipeptide as a possible AdipoR1 agonist.
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