Lemon verbena (Lippia citriodora) polyphenols alleviate obesity-related disturbances in hypertrophic adipocytes through AMPK-dependent mechanisms

doi:10.1016/j.phymed.2015.03.015

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Abstract

Background

There is growing evidence that natural products, mostly plant-derived polyphenols, are important in the relationship between nutrients and health in humans.

Purpose

We aimed to investigate if verbascoside (VB) and other lemon verbena polyphenols could ameliorate obesity-induced metabolic disturbances, as well as their putative mechanism.

Study design

We used an insulin-resistant hypertrophic 3T3-L1-adipocyte model to test the effects of VB or lemon verbena extract on triglyceride accumulation, inflammation and oxidative stress and a murine model of diet-induced obesity to assess the in vivo metabolic response.

Results

Polyphenols decreased triglyceride accumulation, the generation of reactive oxygen species (ROS) and restored mitochondrial membrane potential in adipocytes. The underlying mechanisms seemed to occur via ROS-mediated downregulation of nuclear factor kappa-B transcription factor (NF-κB) and peroxisome proliferator-activated receptor gamma (PPAR-γ)-dependent transcriptional upregulation of adiponectin. We also observed a potent activation of AMP-activated protein kinase (AMPK), the mRNA expression upregulation of PPAR-α and the mRNA expression downregulation of fatty acid synthase. Experiments in mice suggested a significant improvement in fat metabolism.

Conclusion

Decreased lipogenesis, enhanced fatty acid oxidation and the activation of the energy sensor AMPK, probably through activating transcriptional factors, are involved in the observed beneficial effects. VB effects were less potent than those observed with the extract, so a potential synergistic, multi-targeted action is proposed. The polypharmacological effects of plant-derived polyphenols from lemon verbena may have the potential for clinical applications in obesity.

Graphical abstract

Keywords

Verbascoside;
Lippia citriodora;
Adipocyte;
Adiponectin;
AMPK;
Fat metabolism

Abbreviations

LC, Lippia citriodora extract;
VB, verbascoside;
FBS, fetal bovine serum;
IBMX, 3-isobutyl-1-methylxanthine;
DEX, dexamethasone;
NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells;
AMPK, adenosine monophosphate-activated protein kinase;
CCL2, chemokine [C–C motif] ligand 2;
TNF-α, tumor necrosis factor-alpha;
IL-1α, interleukin-1 alpha;
IL-1β, interleukin-1 beta;
IL-6, interleukin 6;
PPAR-γ, peroxisome proliferator-activated receptor gamma;
CCL2/MCP-1, monocyte chemotactic protein-1;
HF, high-fat, high-cholesterol diet;
LDLr^−/−, low density lipoprotein receptor knock-out mice;
PPAR-α, peroxisome proliferator-activated receptor α;
FASN, fatty acid synthase;
FFAs, free fatty acids;
TG, triglycerides;
ROS, reactive oxygen species;
AST, aspartate aminotransferase

: Corresponding author at: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avda. de la Universidad S/N, 03202 Elche, Alicante, Spain. Tel.: +34 96 6658430; fax: +34 96 6658758.

¹: These authors share co-senior authorship.

Cheryl & ethnovet

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Sunday, 17 May 2015