2085-P: Physical Activity Mitigates Genetic Obesity Risk via the Leptin–Adiponectin Axis in Children and Adolescents: Findings from the BCAMS Study and Multiomics Analysis

Introduction and Objective: Genetic susceptibility to obesity is well-known. However, the impact of physical activity (PA) on metabolic health in genetically predisposed individuals remains unclear. We aim to explore how PA interacts with obesity polygenic risk scores (PRS) in children, focusing on the modulation of adipose tissue endocrine function and the underlying mechanisms using multi-omics data. Methods: We enrolled 3,280 schoolchildren from the Beijing Children and Adolescents Metabolic Syndrome Study (BCAMS). PA and lifestyle factors were assessed through questionnaires. Fasting insulin and five adipokines (leptin, adiponectin, RBP-4, FGF21, SPARC) were measured. Genetic risk was assessed via genotyping 14 obesity-related SNPs. Mediation analysis examined the role of adipokine levels in the relationship between exercise-regulated PRS and metabolic risk. Multi-omics data integration included publicly available eQTL, multi-tissue transcriptomics, epigenomics, and proteomics data. Results: Significant interactions existed between the 14-SNP PRS and PA scores on BMI, metabolic health, and adipokine levels (p = 0.001-0.05). Key loci responsive to exercise were identified as ADCY3, GNPDA2, PEPD, MAP2K5, and MC4R. Regular MVPA diminished the predictive effect of the PRS on obesity phenotypes (p> 0.05). The leptin/adiponectin ratio significantly mediates the regulation of genetic risk by exercise (p< 0.05). Multi-omics integration revealed that MAP2K5, GNPDA2, and PEPD increase obesity risk, while ADCY3 provides protection. Moreover, the influence of these genes on weight metrics varied significantly with exercise adjustments; exercise enhances metabolic health by altering gene expression and epigenetic states, influencing adipokine secretion. Conclusion: This study elucidates how PA mitigates the genetic obesity risk via the leptin-adiponectin axis. These insights provide a foundation for precision exercise interventions in childhood obesity management. Disclosure M. Li: None. H. Zhu: None. S. Gao: None. Funding the National Natural Science Foundation of China (82270924, 81970732); National High Level Hospital Clinical Research Funding (2025-PUMCH-C-041, 2022-PUMCH-C-014); Capital's Funds for Health Improvement and Research (2020-2Z-40117); the CAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-016); key program of Beijing Municipal Science & Technology Commission (D111100000611001, D111100000611002).