Sex differences in response to a short-term training program intervention in obese adolescents: a plasma metabolomics study.

Background: This study aims to investigate sex differences in the response to short-term Training Program intervention and the underlying metabolomic mechanisms among obese adolescents.

Methods: A total of 98 obese adolescents underwent a 4-week, strictly controlled short-term Training Program intervention. Pre- and post-intervention measurements included body morphometry, body composition, lipid metabolism, and glucose homeostasis indicators. Plasma samples were analyzed using targeted metabolomics. Linear mixed-effects models (LMM) were employed to identify Sex-differential Responsive Metabolites, with volcano plots utilized to visualize metabolic regulation preferences between sexes. Hierarchical clustering analysis identified co-regulated metabolic modules within the Sex-differential Responsive Metabolites for pathway analysis. Partial least squares (PLS) regression models were constructed separately for males and females to identify metabolic biomarkers capable of predicting changes in clinical indicators.

Results: Post-intervention, both males and females showed significant decreases in weight, body mass index (BMI), chest circumference, waist circumference, hip circumference, waist-to-hip ratio, body water, Body fat mass, fat free mass, skeletal muscle mass, body fat percentage, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) (P < 0.001). Additionally, HOMA-β levels significantly decreased only in females (P = 0.01). After adjusting for developmental maturity and baseline metabolic risk, the improvements in body fat mass and body fat percentage in males were significantly greater than those in females (both P < 0.01), whereas no statistical differences were found in weight and BMI improvements (P > 0.05). The change in HOMA-β differed significantly between sexes (P = 0.031), with females exhibiting a more pronounced downregulation following the intervention. LMM identified 65 Sex-differential Responsive Metabolites. Hierarchical clustering revealed two co-regulated modules: Module 1 showed a strong upward trend in males but a weak response in females, significantly enriched in the linoleic acid metabolism pathway; Module 2 showed a downward trend in both sexes, but the magnitude of downregulation was more pronounced in males, significantly enriched in pathways related to amino acid catabolism and energy metabolism. PLS model analysis indicated that Sex-differential Responsive Metabolites had predictive capacity for male Fasting Blood Glucose (FBG, R²Y = 0.2653,Q² = 0.0091), female FBG (R²Y = 0.3552,Q² = 0.1321), and female LDL-c (R²Y = 0.3895,Q² = 0.1853).

Conclusions: Obese adolescents exhibit significant sexual dimorphism in their response to short-term Training Program. Under the same standardized training program, males achieve greater fat reduction and appear to leverage a synergistic strategy of fatty acid oxidation and protein sparing, whereas females prioritize amino-acid network fine-tuning. Predictive modeling indicates that sex-differential metabolites can predict glucolipid improvements in females. These findings provide a scientific basis for developing sex-differential exercise prescriptions for metabolic health.