AMPK modulatory activity of olive-tree leaves phenolic compounds: Bioassay-guided isolation on adipocyte model and in silico approach

PLoS One. 2017 Mar 9;12(3):e0173074. doi: 10.1371/journal.pone.0173074. eCollection 2017.


Scope: Olive-tree polyphenols have demonstrated potential for the management of obesity-related pathologies. We aimed to explore the capacity of Olive-tree leaves extract to modulate triglyceride accumulation and AMP-activated protein kinase activity (AMPK) on a hypertrophic adipocyte model.

Methods: Intracellular triglycerides and AMPK activity were measured on the hypertrophic 3T3-L1 adipocyte model by AdipoRed and immunofluorescence microscopy, respectively. Reverse phase high performance liquid chromatography coupled to time-of-flight mass detection with electrospray ionization (RP-HPLC-ESI-TOF/MS) was used for the fractionation of the extract and the identification of the compounds. In-silico molecular docking of the AMPK alpha-2, beta and gamma subunits with the identified compounds was performed.

Results: Olive-tree leaves extract decreased the intracellular lipid accumulation through AMPK-dependent mechanisms in hypertrophic adipocytes. Secoiridoids, cinnamic acids, phenylethanoids and phenylpropanoids, flavonoids and lignans were the candidates predicted to account for this effect. Molecular docking revealed that some compounds may be AMPK-gamma modulators. The modulatory effects of compounds over the alpha and beta AMPK subunits appear to be less probable.

Conclusions: Olive-tree leaves polyphenols modulate AMPK activity, which may become a therapeutic aid in the management of obesity-associated disturbances. The natural occurrence of these compounds may have important nutritional implications for the design of functional ingredients.

MeSH terms

  • 3T3-L1 Cells
  • AMP-Activated Protein Kinases / analysis
  • AMP-Activated Protein Kinases / chemistry
  • AMP-Activated Protein Kinases / metabolism*
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Animals
  • Binding Sites
  • Chromatography, High Pressure Liquid
  • Chromatography, Reverse-Phase
  • Gene Expression Regulation / drug effects*
  • Mice
  • Microscopy, Fluorescence
  • Molecular Docking Simulation
  • Olea / chemistry*
  • Olea / metabolism
  • Plant Extracts / analysis
  • Plant Extracts / chemistry
  • Plant Leaves / chemistry
  • Plant Leaves / metabolism
  • Polyphenols / chemistry
  • Polyphenols / isolation & purification
  • Polyphenols / metabolism
  • Polyphenols / pharmacology*
  • Protein Structure, Tertiary
  • Protein Subunits / analysis
  • Protein Subunits / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Triglycerides / analysis
  • Triglycerides / metabolism


  • Plant Extracts
  • Polyphenols
  • Protein Subunits
  • Triglycerides
  • AMP-Activated Protein Kinases

Grant support

This work was supported by the projects BFU2014-52433-C3-2-R, AGL2011-29857-C03-02 (Spanish Ministry of Science and Innovation); projects AGL2015-67995-C3-1-R, AGL2015-67995-C3-2-R, Torres Quevedo grants PTQ-13-06429 and PTQ-14-07243 and scholarship FPU AP2010-2793 from the Spanish Ministry of Economy and Competitiveness (MINECO); P09-CTS-4564, P10-FQM-6563 and P11-CTS-7625 grants from Andalusian Regional Government Council of Innovation and Science; PROMETEO/2016/006, and ACIF/2016/230 from Generalitat Valenciana; CIBER (CB12/03/30038, Fisiopatologia de la Obesidad y la Nutricion, CIBERobn, Instituto de Salud Carlos III).