Multi-tissue transcriptomic landscape reveals synergistic mechanisms of exercise and GLP-1 agonist in ameliorating diabetic phenotypes in db/db mice

Type 2 diabetes mellitus (T2DM) involves coordinated multi-organ metabolic dysfunction, yet the systems-level effects of combined pharmacological and exercise interventions remain unclear. Male db/db mice received semaglutide, high-intensity interval training (HIIT), or both for eight weeks. Multi-organ bulk RNA-seq with qPCR validation and CellChat analysis was performed in heart, kidney, liver, hippocampus, and skeletal muscle. Combined treatment produced the greatest reductions in food intake, body weight, and fasting glucose. Transcriptomic responses were organ-dependent, most pronounced in skeletal muscle and liver. Under combination therapy, DEGs in hippocampus and liver no longer reached thresholds relative to single interventions, consistent with unchanged hippocampal Glp1r and hepatic Plpp7 by qPCR, whereas heart, kidney, and skeletal muscle retained concordant regulation with further reductions in cardiac Cyp2ab1 and renal/muscle Apoa1. Cross-organ analysis identified coordinated modulation of the PPARα–Plin4 axis and suppression of lipid metabolic pathways, confirmed by qPCR. Inter-organ network analysis revealed increased communication numbers but reduced interaction strength under combination therapy. These findings demonstrate organ-specific transcriptional adaptation to combined HIIT and semaglutide.