Abstract
Ampelopsin (APL), a major bioactive constituent of Ampelopsis grossedentata, exerts a number of biological effects. Here, we explored the anti-diabetic activity of APL and elucidate the underlying mechanism of this action. In palmitate-induced insulin resistance of L6 myotubes, APL treatment markedly up- regulated phosphorylated insulin receptor substrate-1 and protein kinase B, along with a corresponding increase of glucose uptake capacity. APL treatment also increased expressions of fibroblast growth factor (FGF21) and phosphorylated adenosine 5’-monophosphate -activated protein kinase (p-AMPK), however inhibiting AMPK by Compound C or AMPK siRNA, or blockage of FGF21 by FGF21 siRNA, obviously weakened APL -induced increases of FGF21 and p-AMPK as well as glucose uptake capacity in palmitate -pretreated L6 myotubes. Furthermore, APL could activate PPAR γ resulting in increases of glucose uptake capacity and expressions of FGF21 and p-AMPK in palmitate -pretreated L6 myotubes, whereas all those effects were obviously abolished by addition of GW9662, a specific inhibitor of peroxisome proliferator- activated receptor –γ (PPARγ), and PPARγsiRNA. Using molecular modeling and the luciferase reporter assays, we observed that APL could dock with the catalytic domain of PPARγ and dose-dependently up-regulate PPARγ activity. In summary, APL maybe a potential agonist of PPARγ and promotes insulin sensitization by activating PPARγ and subsequently regulating FGF21- AMPK signaling pathway. These results provide new insights into the protective health effects of APL, especially for the treatment of Type 2 diabetes mellitus.
Highlights
Insulin resistance is regarded as hallmark for type II diabetes mellitus (T2DM), and plays an important role in the pathogenesis of the disease
We measured the phosphorylated levels of insulin receptor substrate-1 (IRS-1) (p-IRS-1) and Protein kinase B (Akt) proteins which are involved in insulin- signaling pathways
Expressions of p-IRS-1 and pAKT were significantly inhibited by palmitate treatment and those effects were dose- dependently attenuated by APL treatment under insulin-stimulated conditions (Fig 1C and 1D)
Summary
Insulin resistance is regarded as hallmark for type II diabetes mellitus (T2DM), and plays an important role in the pathogenesis of the disease. A large number of experiments have showed that FGF21 knockdown could increase PPARγ sumoylation which resulted in attenuating PPARγ-induced the beneficial insulin-sensitizing effects and increasing the detrimental side effects of the PPARγ agonist rosiglitazone, whereas adding back FGF21 could prevent sumoylation and restore PPARγ activity, FGF21 have been considered as a key mediator of the physiologic and pharmacologic actions of PPARγ [22,23,24,25].numerous investigations have found that FGF21 regulates energy homeostasis through activation of AMP-activated protein kinase (AMPK) signaling pathway [26]. We hypothesized that APL maybe an approaching PPARγ agonist that beneficially improved insulin resistance To clarify this hypothesis, the potential involvement of PPARγ activation and further modulation of FGF21-AMPK signaling pathway was evaluated in the models of skeletal muscle insulin resistance induced by palmitate. For the first time, that APL maybe served as a PPARγ agonists and improved insulin resistance partially via activation of PPARγ and subsequent regulation of FGF21- AMPK signaling pathway
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
