The Potential Synergistic Modulation of AMPK by Lippia citriodora Compounds as a Target in Metabolic Disorders.

Mariló Olivares-Vicente,David Arraez-Roman,Enrique Barrajón-Catalán,Jesús Lozano-Sánchez,Noelia Sánchez-Marzo,Catherine Riva,María De La Luz Cádiz-Gurrea,José Antonio Encinar,Antonio Segura-Carretero,María Herranz-López,Vicente Micol

doi:10.3390/nu11122961

Abstract

Lippia citriodora (LC) represents a complex plant-derived source of polyphenols and iridoids that has shown beneficial properties against obesity-related metabolic disorders. The complete extract and its major compound, verbascoside, have shown AMPK-activating capacity in cell and animal models. In this work, we aimed to elucidate the contribution of the different compounds present in the LC extract on the AMPK activation capacity of the whole extract. Semipreparative reversed-phase high-performance liquid chromatography coupled to electrospray ionization time-of-flight mass spectrometry (RP-HPLC-ESI-TOF-MS) was used to identify the major compounds with bioassay-guided fractionation in an adipocyte cell model for the measurement of AMPK activity. Twenty-two compounds were identified and purified almost to homogeneity in 16 fractions, and three compounds, namely verbascoside, luteolin-7-diglucuronide and loganic acid, showed the highest AMPK-activating capacity. The synergy study using the checkerboard and fractional inhibitory concentration index (FICI) methods exhibited synergistic behavior between loganic acid and luteolin-7-diglucuronide. Molecular docking experiments revealed that these three compounds might act as direct agonists of AMPK, binding to the AMP binding sites of the gamma subunit and/or the different sites of the interaction zones between the gamma and beta subunits. Although our findings conclude that the bioactivity of the extract is mainly due to verbascoside, the synergy found between loganic acid and luteolin-7-diglucuronide deserves further research aimed to develop optimized combinations of polyphenols as a new nutritional strategy against obesity-related metabolic disorders.

Highlights

According to the World Health Organization, the global prevalence of overweight and obesity has tripled in the last four decades
Were collected (Figure 1), and their composition was analyzed by the detailed RP-high-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-TOFwere collected (Figure 1), and their composition was analyzed by the detailed RP-HPLC-ESI-TOF-MS
Previous research has noted that equivalent concentrations of verbascoside in an Lippia citriodora (LC) extract exerted a higher capacity to regulate lipid homeostasis through AMPK-dependent mechanisms than pure verbascoside in cell models, suggesting a putative synergistic pharmacological interaction between verbascoside and other components of the extract

Summary

Introduction

According to the World Health Organization, the global prevalence of overweight and obesity has tripled in the last four decades. A growing number of studies have demonstrated the mechanisms by which plant compounds, especially polyphenols, confer such benefits [6,7,8,9,10,11,12,13]. Approaches such as bioguided fractionation and purification have been used to identify the compounds responsible for the health effects, but are insufficient to resolve the complexity of plant extracts. The characterization of purified compounds from plant extracts is achievable by semipreparative high-performance liquid chromatography (HPLC) coupled to reversed-phase

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Conclusion