The Potential Effects of Exercise Training on Cortical Glutamatergic Synapse, Retrograde Endocannabinoid Signaling, and the Oxytocin Signaling Pathway in the Diabetic–Obesity Cortex: An In Silico Study

Exercise training reduces metabolic dysfunction and improves neural function; however, its cortical molecular effects in diabetic-obese conditions remain unclear. Here, we aimed to identify transcriptional pathways by integrating physiological evaluation with an in silico analysis of cortical RNA-seq data from Zucker Fatty Diabetes Mellitus rats following a 12-week swimming training program. Exercise training reduced body weight and improved glucose control and blood pressure. RNA-seq analysis revealed 814 differentially expressed genes, with pathway enrichment highlighting glutamatergic synapse, retrograde endocannabinoid signaling, and oxytocin signaling pathways. These coordinated transcriptional shifts involved genes related to excitatory neurotransmission, neuromodulatory feedback, and calcium-dependent regulation. As hypothesis-generating models, these pathway-level patterns suggest that exercise training may modulate cortical signaling properties in diabetic-obese states and provide a conceptual framework for future mechanistic investigation.