Antioxidant and Anti-Inflammatory Potential of Polyphenols Contained in Mediterranean Diet in Obesity: Molecular Mechanisms

Abstract

Nutrition transition can be defined as shifts in food habits, and it is characterized by high-fat (chiefly saturated animal fat), hypercaloric and salty food consumption at the expense of dietary fibers, minerals and vitamins. Western dietary patterns serve as a model for studying the impact of nutrition transition on civilization diseases, such as obesity, which is commonly associated with oxidative stress and inflammation. In fact, reactive oxygen species (ROS) overproduction can be associated with nuclear factor-κB (NF-κB)-mediated inflammation in obesity. NF-κB regulates gene expression of several oxidant-responsive adipokines including tumor necrosis factor-α (TNF-α). Moreover, AMP-activated protein kinase (AMPK), which plays a pivotal role in energy homeostasis and in modulation of metabolic inflammation, can be downregulated by IκB kinase (IKK)-dependent TNF-α activation. On the other hand, adherence to a Mediterranean-style diet is highly encouraged because of its healthy dietary pattern, which includes antioxidant nutraceuticals such as polyphenols. Indeed, hydroxycinnamic derivatives, quercetin, resveratrol, oleuropein and hydroxytyrosol, which are well known for their antioxidant and anti-inflammatory activities, exert anti-obesity proprieties. In this review, we highlight the impact of the most common polyphenols from Mediterranean foods on molecular mechanisms that mediate obesity-related oxidative stress and inflammation. Hence, we discuss the effects of these polyphenols on a number of signaling pathways. We note that Mediterranean diet (MedDiet) dietary polyphenols can de-regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and NF-κB-mediated oxidative stress, and metabolic inflammation. MedDiet polyphenols are also effective in upregulating downstream effectors of several proteins, chiefly AMPK.

Keywords: AMPK; MedDiet; NF-κB; inflammation; obesity; oxidative stress; polyphenols.

Figure 1

Graphical summary of some inflammatory and oxidative pathways related to obesity. High glucose intake and FFA-dependent TLR4 activation lead to the activation of NOX, which can also be activated by PKC in adipocytes. NOX mediates intracellular ROS generation, mainly O₂^•−, both in preadipocytes and macrophages. Likewise, mitochondrial ROS exacerbate oxidative stress and inflammatory processes in obesity. JNK mediates ROS and oxidative stress-dependent activation of NF-κB and AP-1. These latters regulate gene expression of TNF-α, IL-6, MCP-1 and PAI-1. The NF‑κB pathway might be upregulated in hypoxic adipose tissue and in response to TNF-α. Furthermore, TNF-α inhibits AMPK pathways, resulting in increased COX-2 and PGE2 and decreased PPARγ. TNF-α and IL-6 secreted from WAT enhance CRP and low-density lipoprotein (LDL) release from the liver in response to hepatic oxidative stress. A crosstalk between adipocytes and resident macrophages reinforces oxidative stress through TNF-α–mediated ROS generation within WAT cells in an autocrine and paracrine manner.

Figure 2

Chemical structure of some dietary polyphenols.

Figure 3

Summary of potential mechanisms by which MedDiet polyphenols modulate oxidative stress and inflammation associated with obesity. MedDiet polyphenols potentiate both AMPK- and Nrf2-mediated anti-inflammatory and antioxidant pathways, reflected by anti-inflammatory adiponectin, PPARγ, and endogenous antioxidants (SOD, GSH, GPx, and GST) upregulation. On the other hand, PKC and NF-κB-dependent inflammation and oxidative stress are counteracted by MedDiet polyphenols, reflected by the downregulation of pro-inflammatory molecules (AP-1, TNF-α, IL-6, IL-1β, MCP-1, VCAM-1, and CRP), and oxidative stress mediators and operators (MD, NOX, iNOS, ROS, MDA).