Mechanisms of Oxidative Stress in Metabolic Syndrome

Abstract

Metabolic syndrome is a cluster of conditions associated with the risk of diabetes mellitus type 2 and cardiovascular diseases (CVDs). Metabolic syndrome is closely related to obesity. Increased adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving metabolic syndrome components, namely insulin resistance, hypertension, and hyperlipidemia. An increasing number of studies confirm the importance of oxidative stress and chronic inflammation in the etiology of metabolic syndrome. However, few studies have reviewed the mechanisms underlying the role of oxidative stress in contributing to metabolic syndrome. In this review, we highlight mechanisms by which reactive oxygen species (ROS) increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant function in metabolic syndrome. Biomarkers of oxidative stress can be used in disease diagnosis and evaluation of severity.

Keywords: cardiovascular disease; hyperglycemia; hyperlipidemia; hypertension; inflammatory cytokines; insulin resistance; metabolic syndrome; obesity; oxidative stress.

Figure 1

Structure of reactive oxygen species and their sources. ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; NOX2, NADPH oxidase.

Figure 2

Sources of reactive oxygen species. SOD2, superoxide dismutase 2; ROS, reactive oxygen species; ER, endoplasmic reticulum; NADPH, nicotinamide adenine dinucleotide phosphate; H₂O₂, hydrogen peroxide.

Figure 3

Mechanisms of metabolic syndrome. Under pathological conditions such as obesity, chronic inflammation, and hyperglycemia, excessive ROS generation can occur. ROS production occurs through the activation of enzymes in the cytosol, membrane, and mitochondria. An increase in the production of ROS and the depletion of antioxidants result in oxidative stress. The resulting oxidative stress leads to intracellular cell damage and altered redox, which leads to the irreversible accumulation of oxidation products, promoting endothelial dysfunction, which leads to insulin resistance, hypertension, dyslipidemia, and, subsequently, metabolic syndrome. ROS, reactive oxygen species; NOX2, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzymes.

Figure 4

Proposed mechanisms of oxidative stress associated with adipocytes. Nutritional excess and adipocyte hypertrophy, as well as the release and accumulation of pro-inflammatory mediators such as free fatty acids (FFA), hyperglycemia, advanced glycation end products, cytokines, and pro-inflammatory cytokines linked to protein kinase C (PKC) and polyol pathways, characterize obesity. By activating NADPH oxidase (NOXs), nitric oxide synthase, uncoupled endothelial NOS (eNOS), and myeloperoxidase, these components may induce tissue oxidative stress. Chronic inflammation may also contribute to the modification of adipose tissue’s redox balance by activating stress signal transduction, which contributes to increased autophagy and apoptosis, uncontrolled adipokine production, and adipose tissue inflammation. The resultant functional changes may further impair adipose tissue function by affecting intracellular pathways that generate pro-inflammatory cytokines, resulting in increased attraction, infiltration, and activation of immune cells, as well as increased adipose tissue inflammation, thereby creating a vicious cycle between adipose tissue oxidative stress and inflammation, as well as a decrease in antioxidant system activity, ultimately leading to metabolic dysfunction. AGEs, advanced glycation end products; PKC, protein Kinase C; NOX, nicotinamide adenine dinucleotide phosphate oxidase enzyme; ER, endoplasmic reticulum; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; ROS, reactive oxygen species; TCA, tricarboxylic cycle; TNF-α, tumor necrosis factor alpha.

Figure 5

Proposed mechanisms of oxidative stress-induced hypertension. The NOX (NADPH oxidase) family and xanthine oxidase enzymes are the principal generators of reactive oxygen species (ROS) in hypertension, and they are regulated by pro-hypertensive and pro-inflammatory factors such as Ang II (angiotensin II) and ET-1 (endothelin-1). eNOS (endothelial nitric oxide synthase) uncoupling and mitochondrial and endoplasmic reticulum (ER) pathways affected by NOX/ROS also result in the production of ROS. These may result in hypertension due to endothelial damage, renal injury, or cardiovascular dysfunction. SOD, superoxide dismutase; NO, nitric oxide; BH4, tetrahydrobiopterin.

Figure 6

Eubiosis and dysbiosis in the gut. In normal conditions, the gut is in a eubiotic state, having a pool of microbes that is mostly composed of non-pathogenic microorganisms that are relevant for normal physiological function, such as promoting physiological cross-talk with other systems such as the brain, cardiovascular organs, and metabolic-related tissues, helping to avoid and fight hypertension and metabolic syndrome progression. The gut microbiota produces compounds beneficial to host intestinal health, which can be regulated through personal nutrition. However, dysbiosis in the gut microbiota (triggered and caused by antibiotics, urban diet, and sedentary lifestyle) is linked to chronic inflammation and exacerbates oxidative stress, consequently leading to metabolic syndrome.