In vitro and in silico characterization of adiponectin-receptor agonist dipeptides

Yuna Lee; Akihiro Nakano; Saya Nakamura; Kenta Sakai; Mitsuru Tanaka; Keisuke Sanematsu; Noriatsu Shigemura; Toshiro Matsui

doi:10.1038/s41538-021-00114-2

In vitro and in silico characterization of adiponectin-receptor agonist dipeptides

NPJ Sci Food. 2021 Nov 12;5(1):29. doi: 10.1038/s41538-021-00114-2.

Authors

Yuna Lee¹, Akihiro Nakano¹, Saya Nakamura¹, Kenta Sakai², Mitsuru Tanaka², Keisuke Sanematsu^{2

3

4}, Noriatsu Shigemura^{2

3}, Toshiro Matsui^{5

6}

Affiliations

¹ Department of Bioresources and Biosciences, Faculty of Agriculture, Graduate School of Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
² Research and Development Center for Five-Sense Devices, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
³ Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
⁴ Oral Health/Brain Health/Total Health Research Center, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
⁵ Department of Bioresources and Biosciences, Faculty of Agriculture, Graduate School of Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. tmatsui@agr.kyushu-u.ac.jp.
⁶ Research and Development Center for Five-Sense Devices, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. tmatsui@agr.kyushu-u.ac.jp.

Abstract

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.

Abstract

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