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Open AccessFeature PaperArticle

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

1
Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Instituto de Biología Molecular y Celular (IBMC), Miguel Hernández University (UMH), 03202 Elche, Spain
2
Department of Analytical Chemistry, University of Granada, 18071 Granada, Spain
3
Research and Development of Functional Food Centre (CIDAF), PTS, 18016 Granada, Spain
4
LaPEC EA4278, Avignon University, 84000 Avignon, France
5
CIBER: CB12/03/30038, Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
These authors shared author co-seniorship.
Nutrients 2019, 11(12), 2961; https://doi.org/10.3390/nu11122961
Received: 4 November 2019 / Revised: 26 November 2019 / Accepted: 29 November 2019 / Published: 4 December 2019
(This article belongs to the Special Issue Dietary Polyphenols and Cardiometabolic Diseases)
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.
Keywords: Lippia citriodora; polyphenol; adipocyte; AMPK; molecular docking; synergy Lippia citriodora; polyphenol; adipocyte; AMPK; molecular docking; synergy
MDPI and ACS Style

Olivares-Vicente, M.; Sánchez-Marzo, N.; Encinar, J.A.; de la Luz Cádiz-Gurrea, M.; Lozano-Sánchez, J.; Segura-Carretero, A.; Arraez-Roman, D.; Riva, C.; Barrajón-Catalán, E.; Herranz-López, M.; Micol, V. The Potential Synergistic Modulation of AMPK by Lippia citriodora Compounds as a Target in Metabolic Disorders. Nutrients 2019, 11, 2961.

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