The Role of Oxidative Stress Enhanced by Adiposity in Cardiometabolic Diseases

The review addresses how adiposity-enhanced oxidative stress contributes to the development and outcomes of cardiometabolic diseases (CVD, MetS, T2D). CMDs are highly prevalent and linked to major risk factors (high blood pressure, elevated glucose, increased BMI). Obesity is common among individuals with T2D, hypertension, and dyslipidemia, and abdominal obesity is frequent in MetS. The purpose is to synthesize current knowledge on redox imbalance stemming from excess adipose tissue, explain mechanistic links to CMDs (endothelial dysfunction, atherosclerosis, insulin resistance), and discuss clinical implications and potential interventions. The study underscores the importance of identifying oxidative stress pathways to improve prevention and therapy for CMDs.

The article is a narrative review integrating findings from basic and clinical studies on: (1) adipose tissue biology and types (white, brown, beige, pink) and depot-specific roles (visceral, epicardial, perivascular, subcutaneous); (2) oxidant–antioxidant systems, sources of reactive oxygen/nitrogen species (mitochondrial respiratory chain, NOX enzymes, NOS, xanthine oxidase, ERO1, peroxisomal β-oxidation, COX/LOX) and antioxidant defenses (SOD, GPx, catalase, glutathione, vitamins C/E, polyphenols); (3) oxidative stress classification by time and intensity, and biomarkers (H2O2, isoprostanes, MDA, 4-HNE, 8-oxodG); (4) adipose tissue as a ROS source in obesity, shifts from NOX4 to NOX2 and mitochondrial dysfunction across obesity stages, and altered adipokines (↑leptin, ↑chemerin; ↓adiponectin, ↓omentin-1) promoting vascular dysfunction; (5) evidence linking oxidative stress to hypertension, atherosclerosis, MetS, coronary artery disease, and clinical outcomes; and (6) therapeutic perspectives including lifestyle, nutraceuticals, and pharmacologic agents with antioxidant properties.

This is a narrative review. The authors synthesize extant evidence from basic science, translational research, and clinical studies on oxidative stress, adiposity, and cardiometabolic diseases. No new experimental or clinical data were collected. The review draws on published observational cohorts, interventional trials, and mechanistic studies to discuss biomarkers of oxidative stress, pathophysiological mechanisms, clinical associations, and therapeutic implications.

- Obesity-driven oxidative stress: Excess adipose tissue increases ROS via mitochondria, NOX enzymes (notably NOX4 in adipocytes and NOX2 in AT macrophages), ERO1, and xanthine oxidase; with progression of obesity, ROS sources may shift from NOX4 to NOX2 to mitochondrial dysfunction. Altered adipokines (↑leptin, ↑chemerin; ↓adiponectin, ↓omentin-1) contribute to endothelial dysfunction, vasoconstriction, and atherogenesis. - Oxidative stress markers are elevated in obesity and CMDs: Isoprostanes (IsoPs), MDA, protein carbonyls, 8-oxodG, and H2O2 are frequently increased in obese individuals, including children, and correlate with blood pressure, central adiposity indices (BMI derivatives, waist circumference), insulin resistance, body fat, lipids, and inflammation (hs-CRP). Some treated hypertensive patients show lower IsoPs than untreated. - Hypertension: IsoPs correlate with systolic/diastolic BP and predict incident hypertension in long-term follow-up (up to 11.5 years). In obese children, peroxy radicals correlate with systolic BP and total cholesterol; total antioxidant capacity is inversely associated with systolic BP and pulse pressure. Some cohorts show no BP–IsoP correlation, but IsoPs correlate with obesity/insulin resistance, suggesting early cardiometabolic dysfunction. - Atherosclerosis and MetS: Oxidative modification of lipoproteins and lipid peroxidation (IsoPs, MDA) promote foam cell formation and endothelial dysfunction. Obesity is associated with higher oxLDL, lower PON-1, and increased NADPH oxidase expression in vascular endothelium. Weight loss through calorie restriction reduces oxidative stress in leukocytes and improves subclinical atherosclerotic markers (small dense LDL, MPO, adhesion). - Coronary artery disease and cardiac tissue: In obese patients undergoing CABG, myocardial tissue shows increased ROS, elevated ROS-producing enzymes (p47phox, XO), reduced antioxidant defenses, inflammation, mitochondrial dysfunction, and telomere shortening indicative of oxidative stress. Obese hearts exhibit reduced metabolic flexibility and enhanced oxidative stress pathways. - Outcomes and mortality: In a 14-year cohort of older adults, urinary 8-isoprostane and oxidized guanine/guanosine independently predicted CVD mortality and stroke; myocardial infarction prediction was significant in obese subjects (BMI ≥30 kg/m2). Adding these biomarkers improved risk prediction over standard scores. - Interventions: Lifestyle and weight loss (dietary restriction, intensive rehabilitation) reduce oxidative stress and improve vascular markers. Plant-derived nutraceuticals (green tea, cocoa, extra virgin olive oil) and vitamin E show improvements in small studies, but large randomized trials do not support vitamins E/C for reducing CVD events. Time-restricted eating has shown reductions in lipid peroxidation and improvements in BP and insulin sensitivity in small studies. Pharmacologic agents with upstream antioxidant effects (ACE inhibitors) and agents with antioxidant properties (GLP-1 receptor agonists, metformin) show mechanistic and preliminary evidence of reducing oxidative stress and protecting endothelium and organs in diabetes and obesity.

The review connects excess adiposity to disordered redox homeostasis as a mechanistic driver of CMDs. Adipose expansion enhances ROS production through mitochondrial overload, NOX activation, and other enzymatic sources, while decreasing antioxidant capacity and altering adipokine profiles. This redox imbalance impairs endothelial function, promotes lipid peroxidation and inflammation, accelerates atherogenesis, and contributes to hypertension, coronary plaque development, and cardiac remodeling. Clinical evidence linking oxidative biomarkers (IsoPs, MDA, 8-oxodG) with BP, central adiposity, dyslipidemia, and incident hypertension supports oxidative stress as a biomarker and potential therapeutic target. Weight loss and lifestyle strategies can mitigate oxidative stress and improve subclinical vascular markers, suggesting a causal role and therapeutic leverage. Pharmacologic strategies that limit ROS generation at the source (e.g., inhibition of angiotensin II pathways) or exert antioxidant effects (GLP-1RA, metformin) may confer benefits beyond glucose and BP control. Nonetheless, mixed results of vitamin supplementation underscore the need for targeted antioxidant approaches aligned with the specific sources and sites of ROS generation.

CMDs are highly prevalent and driven by common risk factors such as high BP, hyperglycemia, and increased BMI. Oxidant–antioxidant imbalance is central to the pathogenesis and outcomes of hypertension, atherosclerosis, CAD, cerebrovascular disease, and MetS. Excess adiposity augments ROS generation in adipose tissue, leading to systemic oxidative stress that contributes to endothelial dysfunction and cardiometabolic complications. Advancing understanding of adiposity-enhanced oxidative stress will inform beneficial lifestyle interventions and novel pharmacotherapies to reduce CMD burden. Further basic research and clinical trials are necessary to elucidate mechanisms and to establish the efficacy of antioxidant strategies for risk reduction and improved outcomes in patients with CMDs.

As a narrative review, the article does not present original data and relies on heterogenous studies with varying designs, populations, and biomarkers. Translational gaps persist between preclinical antioxidant successes and clinical outcomes, attributable to CMD pathophysiological complexity, single-target antioxidant approaches, low bioavailability of natural antioxidants, clinically irrelevant dosing in experimental work, and study designs not reflecting multi-morbidity. Large randomized trials of vitamins E/C have not shown reductions in CVD events, highlighting the challenge of non-targeted antioxidants. There is limited clinical evidence for newer antioxidant strategies (e.g., GLP-1RA, metformin) on hard outcomes, and more rigorous, long-term trials are needed, including standardized biomarker panels and assessments of mitochondrial function.