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

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.

Loganic Acid, an Iridoid Glycoside Extracted from Cornus mas L. Fruits, Reduces of Carbonyl/Oxidative Stress Biomarkers in Plasma and Restores Antioxidant Balance in Leukocytes of Rats with Streptozotocin-Induced Diabetes Mellitus

“…So, this enzyme is sensitive to oxidative-nitrative stress and may undergo ROS-dependent inactivation, thus its activity is decreased. LA showed not only antioxidant properties but also possess anti-inflammatory activity by activation of AMP-activated protein kinase (AMPK) [53]. AMPK is a regulator of metabolic pathways and inflammatory activity in leukocytes.…”

“…LA showed not only antioxidant properties but also possess anti-inflammatory activity by activation of AMP-activated protein kinase (AMPK) [ 53 ]. AMPK is a regulator of metabolic pathways and inflammatory activity in leukocytes.…”

Osteoprotective Effects of Loganic Acid on Osteoblastic and Osteoclastic Cells and Osteoporosis-Induced Mice

“…Loganic acid is one of the main compounds present in GL extract [ 28 ]. Several therapeutic effects of loganic acid have been demonstrated, including inhibitory effects on inflammation [ 33 ], anti-obesity effects [ 34 ], and preventive effects on diet-induced hypertriglyceridemia and atherosclerosis [ 35 ]. However, the protective effects of loganic acid on bone metabolic disorders have not been elucidated yet.…”

Pleiotropic Biological Effects of Dietary Phenolic Compounds and their Metabolites on Energy Metabolism, Inflammation and Aging

“…It was also observed that several compounds showed a synergic behavior, which provided a greater capacity of activation of the AMPK [39]. Similarly, Olivares-Vicente et al (2019) also observed this synergic effect being verbascoside, luteolin-7-diglucuronide and loganic acid the compounds with greatest capacity to activate AMPK in mature adipocytes [39,40]. The mechanism of action by which these compounds exerted this activating action on AMPK could be explained by their direct actuation as agonists of AMPK, linking to the AMP binding sites of the gamma subunit and/or the different sites of the interaction zones between the beta and gamma subunits [40].…”

“…The mechanism of action by which these compounds exerted this activating action on AMPK could be explained by their direct actuation as agonists of AMPK, linking to the AMP binding sites of the gamma subunit and/or the different sites of the interaction zones between the beta and gamma subunits [40]. Since these results showed the ability of L. citriodora compounds to activate the AMPK pathway, this mechanism could be considered a strategy against obesity-related metabolic disorders [39,40].…”