The Potential Synergistic Modulation of AMPK by Lippia citriodora Compounds as a Target in Metabolic Disorders
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AuthorOlivares-Vicente, Mariló; Sánchez Marzo, Noelia; Encinar, José Antonio; Cádiz-Gurrea, María de la Luz; Lozano Sánchez, Jesús; Segura Carretero, Antonio; Arráez Román, David; Riva, Catherine; Barrajón-Catalán, Enrique; Herranz-López, María; Micol Molina, Vicente
Lippia citriodoraPolyphenolAdipocyteMolecular docking
Olivares-Vicente, M., Sánchez-Marzo, N., Encinar, J. A., Cádiz-Gurrea, M. D. L. L., Lozano-Sánchez, J., Segura-Carretero, A., ... & Micol, V. (2019). The Potential Synergistic Modulation of AMPK by Lippia citriodora Compounds as a Target in Metabolic Disorders. Nutrients, 11(12), 2961.
SponsorshipThis work was supported by projects AGL2015-67995-C3-1-R and RTI2018-096724-B-C21 (Spanish Ministry of Economy and Competitiveness), PROMETEO/2016/006 from Generalitat Valenciana and CIBER (CB12/03/30038, Fisiopatologia de la Obesidad y la Nutricion, CIBERobn, Instituto de Salud Carlos III). Scholarships ACIF/2016/230 and APOSTD/2017/023 from Generalitat Valenciana cofinanced with the European Social Fund, and by a grant from the Federative Research Structure TERSYS from Avignon University, France.
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.