Opposing Profiles of Netrin-1 and Adiponectin in Metabolic Inflammation and Insulin Resistance

Maria Guadalupe Ramos-Zavala^1,2Jesus Jonathan García-Galindo^1*Alberto Beltrán-Ramírez¹Luis Ricardo Balleza-Alejandri³Emiliano Peña-Durán⁴Alfredo Huerta Huerta³Edy David Rubio Arellano^1,5Luis Daniel López-Murillo¹Sara Pascoe-Gonzalez⁵Tannia Isabel Campos Bayardo¹Daniel Osmar Suárez Rico^1,3,6

• ¹Departamento de Fisiología, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, México, Guadalajara, Mexico
• ²Institute of Experimental and Clinical Terapeutics (INTEC), Health Science University Center, Universidad de Guadalajara, 44340, Mexico, Guadalajara, Mexico
• ³Hospital Medica de la Ciudad, Santa Catalina, Calle. Pablo Valdez 719, La Perla, Guadalajara 44360, Guadalajara, Mexico
• ⁴Licenciatura en Médico Cirujano y Partero, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Mexico
• ⁵Institute of Experimental and Clinical Terapeutics (INTEC), Health Science University Center, Universidad de Guadalajara, 44340, Guadalajara, Mexico
• ⁶División de Medicina Molecular, Laboratorio de Microbiología Molecular II, CIBO, IMSS, Ap. Postal 1-3838, Guadalajara, Mexico

Obesity is associated with chronic low-grade inflammation that contributes to the development of insulin resistance and metabolic dysfunction. Recent evidence suggests that Netrin-1, originally described as an axonal guidance molecule, also plays a role in immune regulation by promoting macrophage retention in inflamed adipose tissue. This study aimed to evaluate the serum concentrations of Netrin-1, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and adiponectin in individuals with different metabolic profiles-non-obese controls, individuals with preclinical obesity, and individuals with clinical obesity and insulin resistance-and to explore their association with systemic inflammation and early metabolic disturbances. Methods: Cross-sectional study between 2023 and 2024 including 60 participants, control group (C, n = 20) comprised individuals aged 18-35 years with body-fat percentages < 25 % in men and < 35 % in women and a body-mass index (BMI) < 25 kg/m². The two remaining groups were classified according to their Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score into preclinical obesity (PO, HOMA-IR < 2.5; n = 20) and clinical obesity with insulin resistance (CO, HOMA-IR > 2.5; n = 20). Anthropometric indices, fasting glucose/insulin and lipid panel were recorded. Serum Netrin1, adiponectin, IL6 and hsCRP were quantified by sandwich ELISA. Pairwise Wilcoxon tests with Holm correction were performed as post hoc analysis following Kruskal-Wallis; correlations were assessed using Spearman coefficients with 95% confidence intervals. Results: Netrin-1 levels were significantly elevated in participants with obesity and insulin resistance compared to controls (p = 0.013) and showed a positive correlation with hs-CRP (r = 0.34, p < 0.05). In contrast, adiponectin levels declined progressively across groups (p < 0.001) and had an inverse correlation with body fat percentage (r = -0.52), waist circumference (r = -0.43), IL-6 (r = -0.53), and hs-CRP (r = -0.22). Additionally, a negative correlation was observed between Netrin-1 and adiponectin (r = -0.39), suggesting a possible counter-regulatory relationship. Conclusion: These findings indicate that Netrin-1 and adiponectin exhibit opposing behaviors in relation to metabolic impairment and inflammation, positioning them as potential biomarkers and therapeutic targets in the early stages of metabolic disease.