Tissue-Specific Transcriptomics Uncover Exercise-Responsive Immune–Metabolic Regulatory Targets in Obesity

Objectives: Obesity disrupts adipose and systemic immune–metabolic homeostasis, yet the molecular mechanisms through which exercise restores abnormal tissue function remain incompletely defined. This study aimed to screen cross-tissue candidate genes associated with exercise-mediated correction of obesity-related transcriptional disorders via multi-tissue transcriptome profiling and bioinformatic gene prioritization. Methods: Transcriptomic datasets of mouse visceral white adipose, subcutaneous white adipose and skeletal muscle were downloaded from the public GEO database, covering normal control, high-fat induced obese and post-exercise intervention groups. R programming was applied to complete differential analysis, GO/KEGG enrichment, PPI network, LASSO and GSEA; independent human adipose datasets from GEO validated candidate genes. Results: Exercise reversed obesity-triggered transcriptional changes in adipose tissues. Exercise-responsive genes concentrated on immune inflammation, lipid and energy metabolism. Key hub genes for tissue remodeling were screened, and depot-specific pathway regulation was verified by GSEA. CCL2 showed consistent expression trends across mouse and human adipose data. Conclusions: This study identifies distinct tissue-specific transcriptional responses to exercise: visceral adipose mainly achieves reversal of obesity-induced inflammatory dysregulation, subcutaneous adipose undergoes combined immune–inflammatory and metabolic reprogramming, while skeletal muscle presents only energy-metabolism adaptive remodeling without obvious reversal of obese gene disorders. Immune–metabolic pathways dominate exercise-induced restoration in adipose tissues. Integrated network screening and cross-species validation identified CCL2 as a conserved candidate associated with exercise-responsive immune–metabolic pathways, providing valuable molecular candidates for further anti-obesity research.