The Role of Oxidative Stress Enhanced by Adiposity in Cardiometabolic Diseases

Cardiometabolic diseases (CMDs) represent a significant global health burden, with cardiovascular disease (CVD), metabolic syndrome (MetS), and type 2 diabetes (T2D) as major contributors to morbidity and mortality. CVD, particularly coronary artery disease (CAD) and systemic essential hypertension (HTN), are leading causes of premature death in developed nations. The prevalence of HTN is substantial, increasing with age and posing a considerable cardiovascular risk. MetS, affecting a large portion of the adult population, significantly increases the risk of CVD and T2D. The incidence of T2D is continuously rising, further exacerbating the CMDs epidemic. The global prevalence of obesity, MetS, and T2D has increased dramatically over recent decades, largely driven by risk factors such as high systolic blood pressure, elevated plasma glucose, and increased BMI. While lifestyle modifications and pharmacologic interventions are employed, their effectiveness remains insufficient. Obesity is a major risk factor for metabolic disorders like MetS and T2D, and a primary driver of CVD-related mortality and disability. The rising prevalence of obesity has outpaced the growth in related disease burden, highlighting the need to understand the underlying mechanisms. Oxidative stress, an imbalance between reactive oxygen species (ROS) generation and antioxidant defenses, plays a crucial role in the pathophysiology of obesity, atherosclerosis, and CMDs. ROS and redox signaling are fundamental to various cellular processes; however, excessive ROS can damage cellular components, leading to various disorders. Oxidative stress is a common feature of HTN, CAD, stroke, and MetS, contributing to endothelial damage, vascular dysfunction, inflammation, and impaired insulin signaling. The interaction between adiposity, oxidative stress, and CMDs requires further investigation to develop effective prevention and treatment strategies.

The review extensively cites existing literature on the relationship between adiposity, oxidative stress, and cardiometabolic diseases. It covers various aspects of adipose tissue biology, including the different types of adipose tissue (WAT, BAT, beige, and pink) and their roles in energy storage, metabolism, and inflammation. The review discusses the mechanisms by which obesity leads to increased oxidative stress, focusing on the role of mitochondria, NADPH oxidase, and other sources of ROS in adipose tissue. A significant portion of the literature review examines the clinical implications of oxidative stress in CMDs, specifically in hypertension, atherosclerosis, coronary artery disease, and metabolic syndrome. The studies reviewed include both animal models and human clinical trials exploring the association between oxidative stress markers (e.g., isoprostanes, malondialdehyde, 8-hydroxy-2'-deoxyguanosine) and cardiometabolic parameters, including blood pressure, lipid profiles, and insulin resistance. The role of adipokines (leptin, adiponectin, chemerin, omentin-1) in the development of oxidative stress and inflammation is also discussed. The literature review emphasizes the need for further research to fully elucidate the complex interplay between adiposity, oxidative stress, and CMDs and to assess the efficacy of antioxidant therapies.

This is a review article. The methodology involves a comprehensive search and analysis of existing literature from basic and clinical studies focusing on the relationship between adiposity-enhanced oxidative stress and cardiometabolic diseases. The authors do not describe specific databases searched, search terms, or inclusion/exclusion criteria, which is a limitation of this type of study. However, they state that the review includes results from basic and clinical studies which specifically addresses various aspects of oxidant-antioxidant balance disorders in the course of CMDs in subjects with excess adipose tissue accumulation. The review organizes the existing knowledge into sections on characteristics of adipose tissue, the oxidant-antioxidant balance and oxidative stress, adipose tissue as a source of free radicals, oxidative stress in cardiometabolic disorders in subjects with obesity, and clinical perspectives on managing oxidative stress in CMDs. The authors synthesized information from numerous studies, highlighting common findings and areas of uncertainty. The review article does not include original research data but rather presents a synthesis of previously published studies. The authors aimed to give a comprehensive overview of existing knowledge, identify knowledge gaps, and offer future perspectives for further basic and clinical research.

The review highlights several key associations: 1. **Obesity and Oxidative Stress:** Obesity is strongly linked to increased oxidative stress due to the enhanced production of reactive oxygen species (ROS) within adipose tissue. Mitochondria and NADPH oxidases are identified as primary sources of ROS in adipocytes, with their activity increasing in the presence of excess nutrients. 2. **Oxidative Stress and CMDs:** Oxidative stress is a common feature of various CMDs, including hypertension, atherosclerosis, coronary artery disease, and metabolic syndrome. It contributes to endothelial dysfunction, vascular damage, inflammation, and impaired insulin signaling. 3. **Oxidative Stress Markers:** Several studies examined associations between various oxidative stress markers (isoprostanes, malondialdehyde, 8-hydroxy-2'-deoxyguanosine, etc.) and cardiometabolic parameters in obese individuals. Elevated levels of these markers were frequently observed in obese individuals with CMDs compared to non-obese controls. 4. **Adipokines:** The imbalance of adipokine secretion in obese individuals—increased pro-inflammatory adipokines (leptin, chemerin) and decreased anti-inflammatory adipokines (adiponectin, omentin-1)—contributes to the systemic inflammatory and oxidative stress state observed in CMDs. 5. **Hypertension:** Studies showed positive correlations between oxidative stress markers and blood pressure values, particularly in obese individuals. Isoprostanes, markers of lipid peroxidation, were often associated with hypertension development and progression. 6. **Atherosclerosis and Metabolic Syndrome:** Oxidative stress plays a crucial role in the development and progression of atherosclerosis, linking obesity, particularly central obesity, to atherosclerotic CVD. Oxidative modification of lipoproteins and endothelial dysfunction are key mechanisms involved. 7. **Coronary Artery Disease:** Increased oxidative stress in the heart tissue of obese CAD patients was observed, suggesting that mitochondrial dysfunction contributes to cardiac damage. 8. **CVD Outcomes and Mortality:** Oxidative stress markers were shown to be independent predictors of CVD-related mortality and stroke incidence in some studies, particularly in obese individuals. 9. **Therapeutic Interventions:** Lifestyle interventions (weight loss, dietary modifications, time-restricted eating) and some medications (ACE inhibitors, GLP-1 receptor agonists, metformin) may improve oxidative stress and reduce cardiometabolic risk. However, large-scale clinical trials are needed to confirm the long-term benefits of these approaches.

The review's findings strongly support the critical role of oxidative stress, exacerbated by adiposity, in the pathogenesis and progression of cardiometabolic diseases. The consistent association between oxidative stress markers and various cardiometabolic parameters across multiple studies emphasizes the importance of considering oxidative stress in the management of CMDs. The review highlights the complex interplay between adipose tissue biology, oxidative stress, and inflammation in driving the development of CMDs. The significant associations between oxidative stress markers and CVD outcomes underscore the potential of using these markers as predictors of risk and as targets for therapeutic interventions. While the review presents promising evidence for lifestyle interventions and certain medications in mitigating oxidative stress, the limited clinical evidence on the efficacy of specific antioxidant therapies emphasizes the need for further research. The findings underscore the importance of integrating strategies targeting oxidative stress into comprehensive management plans for patients with CMDs.

This review emphasizes the significant contribution of adiposity-enhanced oxidative stress to the development and progression of cardiometabolic diseases. The observed associations between oxidative stress markers and adverse cardiovascular outcomes highlight the importance of further research to understand the underlying mechanisms and develop effective prevention and treatment strategies. Future studies should focus on large-scale clinical trials to evaluate the efficacy of antioxidant therapies and investigate the potential of oxidative stress markers as predictive tools for identifying individuals at high risk of developing or progressing CMDs. Further research is needed to determine the optimal protocols for lifestyle interventions and pharmacological treatments targeting oxidative stress in the context of managing CMDs.

As a review article, the study is limited by the availability and quality of existing literature. The authors did not specify their search strategy, potentially limiting the comprehensiveness of the review. The interpretation of the findings is also influenced by the heterogeneity of study designs and populations across the reviewed studies. The review does not offer a critical appraisal of the individual studies, potentially overlooking biases or methodological limitations in the primary studies. Furthermore, the absence of original data prevents definitive conclusions regarding causality between adiposity-enhanced oxidative stress and CMDs.