The effects of combined functional and aerobic training along with folic acid supplementation on serum levels of Isthmin-1, inflammatory markers and insulin resistance in men with obesity

Obesity is a complex systemic metabolic disorder characterized by chronic low-grade inflammation and insulin resistance. This study aimed to investigate the effects of a 12-week intervention combining functional and aerobic training with folic acid supplementation on serum levels of Isthmin-1 (ISM1), key inflammatory markers (MCP-1, TNF-α, IL-6), and insulin resistance in young men with obesity. In this double-blind randomized experimental trial, 44 men with obesity (age: 23–32 years, BMI ≥ 30 kg/m²) were randomly allocated into four equal groups ( n = 11 per group): Control (CG), Folic Acid Supplementation (S), Combined Training (CT), and Combined Training + Supplementation (CTS). The training protocol consisted of 12 weeks of progressive functional exercises (focusing on stability, strength, and interval training) combined with treadmill-based aerobic exercise. The supplemented groups consumed 500 μg of folic acid daily. Blood samples were collected 48 h before the initiation and 48 h after the completion of the 12-week intervention to assess biochemical, inflammatory, and glycemic indices. Data were analyzed using a 2×4 mixed-design repeated measures ANOVA, followed by Bonferroni post-hoc pairwise comparisons, with the significance level set at P < 0.05. Body weight and BMI decreased significantly only in the CTS group ( P = 0.001). While both the CT and CTS groups exhibited significant reductions in body fat percentage and fat mass, the magnitude of these reductions was significantly greater in the CTS group ( P = 0.001). Regarding glycemic control, all three active intervention groups (S, CT, and CTS) demonstrated significant reductions in fasting glucose, insulin, and HOMA-IR, with the most pronounced improvements observed in the CTS group ( P < 0.05). Serum ISM1 levels increased significantly in both the CT and CTS groups (P < 0.05), whereas serum levels of MCP-1, TNF-α, and IL-6 decreased significantly in all three intervention groups ( P = 0.001). Furthermore, serum ISM1 levels exhibited a significant inverse correlation with both inflammatory markers and insulin resistance indices. The findings suggest that 12 weeks of combined functional and aerobic training with folic acid supplementation may offer potential benefits for improving metabolic status and insulin sensitivity in obese men; however, these preliminary outcomes should be interpreted with caution due to the limited sample size. https://www.ncbi.nlm.nih.gov/mesh/68009765 . https://www.ncbi.nlm.nih.gov/mesh/68015444 . https://www.ncbi.nlm.nih.gov/mesh/68005492 . https://www.ncbi.nlm.nih.gov/mesh/68007249 . https://www.ncbi.nlm.nih.gov/mesh/68007333 . https://www.ncbi.nlm.nih.gov/mesh/2007061 . The trial was prospectively registered at the Iranian Registry of Clinical Trials ( https://fa.irct.ir/trial/87438 (accessed on 26 November 2025) under registration number (IRCT20120129008863N15).