Oxidative Stress, Inflammation, and Obesity: Insights into Mechanism and Therapeutic Targets ^†

Abstract

Due to being correlated with metabolic syndrome, diabetes mellitus, cardiovascular disease, fatty liver disease, and cancer, obesity is a global health issue that predisposes those affected to morbidity and mortality. Obesity can be defined as an excessive amount of fat accretion in the body. According to current research, visceral adipose tissue performs a critical function as an active endocrine organ due to its function in releasing adipokines that facilitate complex physiological events. These adipokines exacerbate both low-grade inflammation and oxidative stress (OS), two key constituents of obesity-related comorbidities. This review summarizes the most recent data on the relationship between inflammation, OS, and diseases linked to obesity, focusing on how OS overexpression causes cellular damage by weakening antioxidant mechanisms. To understand the mechanisms by which OS is related to comorbidities, we assess a wide range of models, including animal models, biochemical analysis, and clinical research. The most important discoveries are that heightened OS exacerbates inflammation and cellular damage by increasing the formation of ROS and weakening antioxidant defenses. Increased lipid peroxidation and oxidative damage in adipose tissue associated with insulin resistance and metabolic dysfunction have been identified through data from research conducted on KKAy mice, a model of diabetes obesity. Adipokines, like adiponectin, have been shown to have protective functions against inflammation and OS. Thereby, some of these candidates may become promising therapeutic targets. Understanding the mechanism of these systems is a must for developing therapies to decrease OS, restore antioxidant balance, and reprogram inflammatory pathways. Such tactics may further augment clinical outcomes and reduce the occurrence of obesity-associated diseases in global populations. Unlike previous reviews, this work bridges basic mechanisms and therapeutic implications, with a unique emphasis on translational barriers and future clinical directions.

1. Methodology of Literature Search

To enhance transparency, a PRISMA-style approach was adopted to structure the literature selection process. A total of 110 records were initially identified through PubMed, Scopus, and Web of Science using targeted keywords such as obesity, oxidative stress, inflammation, adipokines, and therapeutic targets. After removing duplicates and screening titles and abstracts, 45 articles were reviewed in full, of which 30 studies offering mechanistic or therapeutic insights were included in the final analysis. These included 10 clinical studies, 11 animal model studies, and 9 in vitro or biochemical analysis. To ensure the inclusion of recent and relevant findings, priority was given to the peer-reviewed literature published between 2015 and 2025, while earlier foundational studies were cited only when essential for historical or conceptual clarity.

2. Introduction

Obesity (BMI > 30) is more than excessive fat accumulation—it reflects a chronic state of redox imbalance and inflammation [1,2,3]. Visceral adiposity secretes cytokines such as TNF-α and IL-6, while adiponectin levels decrease, disturbing metabolic homeostasis [4,5]. ROS generation from metabolic overload activates inflammatory signaling (e.g., NF-κB, JNK) and impairs mitochondrial function, leading to insulin resistance and cardiovascular dysfunction [6].

While oxidative stress in obesity is also implicated in neurological and cognitive disorders, this review specifically focuses on systemic and metabolic comorbidities, such as insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease.

3. Pathophysiology of Obesity

Obesity affects different adipose tissue depots in distinct ways. White adipose tissue (WAT), the main fat storage site, undergoes hypertrophy in obesity, which contributes to inflammation and insulin resistance [7]. In contrast, brown adipose tissue (BAT) participates in thermogenesis via uncoupling protein 1 (UCP1) and is considered metabolically protective [8]. A third form, known as beige fat, emerges from WAT under stimuli such as cold exposure or exercise and has gained attention as a potential therapeutic target due to its intermediate characteristics [9].

These fat depots collectively influence energy balance and metabolic regulation, and their dysfunction plays a key role in the development of insulin resistance in obesity.

Key Molecules:

Several key molecules mediate the link between adipose dysfunction and metabolic complications. Leptin levels rise with obesity; however, leptin resistance often develops, reducing its efficacy in appetite regulation [10]. Conversely, adiponectin levels decline in obesity, despite its known anti-inflammatory and insulin-sensitizing effects [11]. Pro-inflammatory cytokines such as TNF-α, IL-6, and resistin are elevated, contributing to chronic inflammation and insulin resistance [12]. At the intracellular level, transcription factors like NF-κB and reactive oxygen species (ROS) amplify cytokine production and immune activation, further worsening metabolic disruption.

4. Oxidative Stress in Obesity

OS reflects an imbalance between ROS and antioxidants. Mitochondrial dysfunction and ER stress under obesity enhance ROS generation, disrupting autophagy and cellular homeostasis [13].

Lipid peroxidation, protein oxidation, and DNA damage are common.

Antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) are significantly reduced in obese individuals [14]. Additionally, glutathione peroxidase (GPx) depletion has also been observed, contributing to oxidative imbalance.

The imbalance between ROS production and antioxidant defense results in oxidative damage to cellular components, contributing to metabolic disturbances.

5. Inflammatory Pathways and Adipokines

Adiponectin counters inflammation by activating AMPK and PPAR-α, enhancing lipid metabolism and suppressing ROS [15]. In contrast, TNF-α and IL-6 increase under obesity.

Adiponectin levels fall, amplifying insulin resistance and oxidative imbalance.

NF-κB and JNK signaling pathways perpetuate inflammatory cytokine production [16].

These pathways highlight the crosstalk between oxidative stress and chronic inflammation mediated by adipokine imbalance in obesity.

6. Experimental and Clinical Evidence

6.1. Animal Models

• ROS in obese mice (KKAy model): In obese KKAy mice, excessive ROS generation in white adipose tissue leads to reduced adiponectin levels and the development of insulin resistance, closely mimicking human metabolic syndrome [17].

The KKAy mouse model is a well-established tool for studying obesity-induced oxidative stress and insulin resistance. Genetic predisposition, combined with excessive caloric intake, leads to visceral fat accumulation and adipose tissue hypertrophy. This expansion induces mitochondrial dysfunction and the overproduction of reactive oxygen species (ROS), causing oxidative damage and the suppression of adiponectin secretion. The resulting decrease in adiponectin triggers elevated TNF-α and IL-6 levels, activating pro-inflammatory pathways like NF-κB. These events collectively impair insulin receptor signaling and promote systemic insulin resistance, effectively mirroring the metabolic disturbances seen in human obesity.

Adiponectin-deficient mice developed insulin resistance upon high-fat feeding, providing strong evidence for adiponectin’s protective role in oxidative and metabolic regulation [18].

Mice fed a high-fat diet developed adipose tissue fibrosis and inflammation via TGF-β signaling, which further exacerbated oxidative stress and insulin resistance [19].

6.2. Human Studies

• Oxidative stress and insulin resistance in obese men: A clinical study of Japanese men showed that levels of the oxidative stress marker 8-epi-prostaglandin F2α were significantly elevated in individuals with high BMIs and insulin resistance, suggesting a direct link between obesity-induced oxidative stress and impaired insulin action [20].
• Systemic oxidative stress in obesity (Framingham Study): Data from a large population-based cohort demonstrated that individuals with higher BMIs exhibited increased levels of plasma oxidized LDL and reduced antioxidant capacity, establishing obesity as a systemic pro-oxidative state [21].
• TNF-α and oxidative stress in obese humans: Obese individuals exhibit significantly elevated serum TNF-α levels and oxidative stress markers, such as lipid peroxides, highlighting the coexistence of inflammation and oxidative imbalance in obesity [22].

6.3. Biochemical Markers

• ROS and antioxidant imbalance in metabolic syndrome: Oxidative stress contributes to insulin resistance by impairing insulin receptor signaling and also promotes β-cell dysfunction and endothelial damage through excessive ROS production [22].
• ROS, inflammation, and metabolic markers: Elevated markers such as MDA and 8-OHdG, along with reduced antioxidant enzymes like SOD and GPx, have been observed in patients with metabolic syndrome, supporting the role of oxidative stress as a central mechanism in obesity-related disorders [23].
• While findings from animal models, such as KKAy mice or adiponectin-deficient mice, offer critical mechanistic insights, they may not fully translate to human physiology due to species-specific differences in adipokine expression, metabolic responses, and oxidative stress regulation. Therefore, caution must be exercised when extrapolating preclinical data to clinical outcomes, emphasizing the need for well-designed human studies to validate these findings.

Table 1. Summary of experimental models assessing oxidative stress in obesity.

Model Type	Population/Model	Parameters	Findings	References
Animal	KKAy mice	ROS, MDA, SOD, GSH	Insulin resistance, OS elevation	[14]
Animal	Adiponectin KO mice	Adiponectin, Insulin	Increased insulin resistance	[18]
Animal	High-fat diet mice	TGf-β, fibrosis	Fibrosis, inflammation	[19]
Human	Obese men	8-epi-PGF2α, HOMA-IR	OS correlates with insulin resistance	[20]
Human	Framingham cohort	OxLDL, antioxidant levels	Higher BMI = higher OS	[21]
Human	Obese adults	TNF-α, lipid peroxides	Inflammatory OS profile	[22]

presents a summary of experimental models that have been used to assess oxidative stress in the context of obesity.

7. Comorbidities of Obesity

Obesity-induced oxidative stress plays a central role in the development of various comorbidities. In type 2 diabetes mellitus (T2DM), ROS interferes with insulin receptor substrate-1 (IRS-1) signaling, resulting in impaired insulin action and glucose uptake. In cardiovascular disease (CVD), oxidative damage impairs endothelial function, promoting atherogenesis and vascular dysfunction. Similarly, in non-alcoholic fatty liver disease (NAFLD), ROS and mitochondrial damage contribute to hepatic inflammation and fibrosis. Chronic oxidative stress also facilitates carcinogenesis, particularly in the liver, breast, and colon, by promoting DNA damage and disrupting cellular regulatory mechanisms [24].

8. Therapeutic Strategies

Despite the preclinical promise of antioxidant and adipokine-targeted therapies, their clinical translation faces significant challenges. Human trials involving antioxidants such as resveratrol and NAC have shown variable outcomes due to differences in dosage, duration, and participant metabolic profiles. Adherence to antioxidant regimens and a lack of standardized biomarkers also hinder the consistency of results. Similarly, although GLP-1 agonists and SGLT2 inhibitors demonstrate OS-lowering effects in short-term studies, comprehensive long-term data are lacking. Moreover, the effectiveness observed in animal models does not always translate to human populations, largely due to species-specific differences in adipokine activity, oxidative stress response, and immune regulation. Therefore, future research should emphasize stratified trial designs, integrate biomarker-based endpoints, and account for variability in patient phenotypes.

Polyphenols, such as resveratrol, have demonstrated antioxidant potential in both preclinical and clinical studies.

• Antioxidants: vitamins C and E, resveratrol, and NAC improve redox status [25].
• Adipokine Modulation: pioglitazone increases adiponectin, improving insulin sensitivity [26].
• Lifestyle: exercise and antioxidant-rich diets reduce ROS and improve inflammatory profiles [27].
• Novel Agents: GLP-1 agonists and SGLT2 inhibitors demonstrate OS-lowering effects [28].

Although antioxidant therapies such as resveratrol and N-acetylcysteine (NAC) have shown potential in preclinical studies, clinical trials have reported inconsistent outcomes due to factors like poor bioavailability, variable dosing, and short treatment durations [28]. For instance, some randomized controlled trials observed modest reductions in oxidative biomarkers, while others found no significant metabolic improvements. Similarly, GLP-1 receptor agonists and SGLT2 inhibitors have demonstrated oxidative stress-lowering effects in certain trials [29,30], but their long-term benefits specifically targeting redox pathways remain under investigation. These inconsistencies highlight the need for standardized trial designs, reliable oxidative stress biomarkers, and stratification based on patient phenotypes to improve translational relevance [31].

9. Conclusions

Obesity is a worldwide public health problem with close association with oxidative stress and low-grade chronic inflammation, both of which have significant roles in the development and establishment of comorbid conditions like type 2 diabetes, cardiovascular disease, NAFLD, and certain types of cancers. Evidence from animal models—i.e., the KKAy diabetic mouse—clinical studies provides evidence that obesity is underlain by excessive generation of reactive oxygen species (ROS), peroxidation of lipids, and disrupted antioxidant defense, both contributing to tissue injury and metabolic disturbance. In addition, the adipokine dysregulation, specifically decreased levels of protective adiponectin, additionally increases inflammatory and oxidative pathways. As demonstrated by experimental and clinical research, increased oxidative stress aggravates insulin resistance and enhances tissue-level dysfunction. Knowledge of these interlinked processes is not only crucial for discovering relevant biomarkers but also for creating therapeutic approaches that restore antioxidant balance and adjust inflammatory responses.

10. Future Directions

Although recent evidence confirms the major involvement of oxidative stress and inflammation in obesity-induced metabolic derangement, more research is necessary to translate these observations into clinical practice. The therapeutic potential of adipokine-targeted therapies, particularly those aimed at adiponectin, is promising but needs more extensive research to establish efficacy and safety in humans.

Also, antioxidant therapy is a potential means to prevent oxidative damage and re-establish redox balance but is subject to rigorous long-term clinical trials to evaluate its effect on obesity and related comorbidities. Exploring these treatments in different populations and metabolic phenotypes will assist in the determination of the most sensitive groups.

To enhance clinical translation, future research should also address patient heterogeneity through stratified approaches. Differences in metabolic phenotypes, gender-specific hormone interactions, and age-related redox dynamics may influence therapeutic outcomes. Integrating emerging tools such as genomics, metabolomics, and proteomics (“omics”) could help identify individualized oxidative stress signatures. Additionally, artificial intelligence (AI) and machine learning algorithms may accelerate biomarker discovery, enabling the real-time prediction of treatment responses and disease risks. Emphasizing personalized intervention strategies may improve therapeutic precision and overcome the variability observed in current trials.

Future research should also involve the discovery of new molecular targets that control oxidative stress pathways and inflammatory mediators. Long-term clinical studies should be conducted to assess the consequences of such interventions and to identify their efficacy in preventing or reversing metabolic diseases associated with obesity.

11. Future Perspective

Tackling obesity requires a multi-dimensional approach that integrates molecular research with translational clinical strategies. Future investigations should not only focus on identifying novel biomarkers and signaling targets related to oxidative stress and inflammation but also prioritize personalized medicine. Stratifying patients based on metabolic phenotype, adipokine levels, and antioxidant capacity may lead to more tailored and effective therapeutic interventions.

Furthermore, the integration of dietary, lifestyle, and pharmacological interventions targeting oxidative stress must be evaluated in diverse populations with long-term outcome studies. The development of dual-action agents—those that restore antioxidant defense while modulating inflammatory adipokines—represents a promising frontier. With obesity contributing significantly to non-communicable diseases worldwide, accelerating translational research from bench to bedside remains an urgent global priority.