Netrin 4: A Novel Cytokine Linked to Oxidative Stress and Insulin Resistance in Obesity, New Study Finds

Han Dai, Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China, and colleagues conducted an in-depth investigation using genome-wide association studies (GWAS), bioinformatics tools, and clinical data to explore the metabolic implications of NTN4.

The study included 404 women: 211 healthy individuals and 193 classified as overweight or obese (OW/OB). Serum levels of NTN4 were assessed using enzyme-linked immunosorbent assay (ELISA), while additional metabolic challenges such as cold exposure, acute exercise, lipid infusion, oral glucose tolerance test (OGTT), and euglycemic-hyperinsulinemic clamp (EHC) were used to observe changes in NTN4 concentrations under varying physiological conditions.

Key Findings:

• The analysis found a significant link between NTN4 and markers of energy metabolism and oxidative stress.
• Individuals with obesity and insulin resistance (IR) had notably higher circulating NTN4 levels than healthy individuals.
• Elevated NTN4 levels positively correlated with key indicators of obesity.
• Higher NTN4 levels were also associated with impaired glucose and lipid metabolism.
• NTN4 levels showed a positive correlation with insulin sensitivity and sex hormone levels.

The authors suggest that these findings position NTN4 as a potential biomarker for metabolic dysregulation. Importantly, the association between increased NTN4 levels and insulin resistance could offer new insights into the early detection and monitoring of metabolic syndrome and related conditions. Despite its known role in vascular and neural development, this is the first study to demonstrate NTN4’s relevance in the pathophysiology of metabolic disease.

While the biological mechanisms underpinning NTN4’s influence remain to be fully elucidated, the results indicate that NTN4 may be involved in the body’s response to metabolic stressors, potentially acting as both a marker and a mediator of insulin resistance.

The study authors emphasized the need for further research to validate NTN4’s clinical utility and to understand whether modulation of NTN4 levels could have therapeutic implications in managing obesity-associated metabolic complications.

In summary, the investigation introduces Netrin 4 as a novel player in the intricate relationship between oxidative stress and insulin resistance, opening new avenues for research and possible intervention in obesity-linked metabolic disorders.

Reference:

Dai, H., Zhang, S., Tian, M., Yang, P., Yang, G., Li, L., Liu, D., Li, K., Li, S., & Yang, M. (2025). Netrin 4 is a novel cytokine associated with oxidative stress and insulin resistance in obese individuals. Diabetes Research and Clinical Practice, 223, 112166. https://doi.org/10.1016/j.diabres.2025.112166