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.
Highlights
Appropriate blood glucose control may help prevent the increasing onset of non-insulin-dependent type II diabetes (NIDDM)[1]
We attempted to discover adiponectin receptor 1 (AdipoR1) agonistic dipeptides, since the structural features of AdipoRon with characteristic 1-benzyl 4-substituted 6-membered cyclic amine moieties and aromatic rings linked with amide bonds (Fig. 1a)[7] can be mimicked by a peptide skeleton-bearing aromatic rings and peptide bonds
AdipoRon, an adiponectin receptors (AdipoR) agonist, was designed to exert an adiponectin-like effect by its characteristic 1-benzyl 4-substituted six-membered cyclic amine moiety and aromatic rings linked with amide bonds (Fig. 1)[7]
Summary
Appropriate blood glucose control may help prevent the increasing onset of non-insulin-dependent type II diabetes (NIDDM)[1]. Alternative medicinal food intake, similar to a daily intake of acarbose, an anti-hyperglycemic drug[2]; promoting glucose availability in exercise would be acceptable for appropriate management of blood glucose levels at early stages of prediabetes. Studies of alternative medicinal foods have demonstrated possible improvement of impaired glucose availability by stimulating adenosine monophosphate-activated protein kinase (AMPK)-mediated glucose transporter 4 (Glut4) translocation pathways independent of the insulin/phosphatidylinositol 3-kinase (PI3K)/Akt-mediated Glut[4] translocation pathways[4,5]. In rat skeletal muscle L6 cell experiments, theasinensins, condensed catechins, promoted glucose uptake through the calcium-calmodulin-dependent protein kinase kinase (CaMKK)/AMPK-mediated Glut[4] translocation pathway[4]. Activating noninsulin AMPK signaling pathways by any bioactive compound may be beneficial for preventing NIDDM in an insulin-independent manner
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