Aerobic training and cannabidiol activate the PI3K/AKT/PDX1 axis to ameliorate beta-cell dysfunction in a rat model of diet-induced obesity.

Abstract

BACKGROUND: This study investigated the therapeutic potential of cannabidiol (CBD) and aerobic training (AT), both alone and in combination, to ameliorate beta-cell dysfunction in a rat model of diet-induced obesity, with a specific focus on the phosphatidylinositol 3-kinase (PI3K)/ protein Kinase B (AKT)/pancreatic and duodenal homeobox 1 (PDX1) pathway. METHODS: Thirty-two male Wistar rats were fed a high-fat diet (HFD) for 8 weeks to induce obesity. They were then randomly assigned to four groups (n&#x2009;=&#x2009;8/group): HFD (sedentary), HFD&#x2009;+&#x2009;CBD (10&#xa0;mg/kg, 5x/week), HFD&#x2009;+&#x2009;AT (30-minute treadmill running,50-80% maximal speed, 5x/week, 8 week), and HFD&#x2009;+&#x2009;CBD+AT (combined treatment) for a further 8 weeks. Following the intervention, beta-cell function was assessed via the HOMA-Beta index, and pancreatic gene expression of PI3K, AKT, and PDX1 was analyzed using RT-PCR. RESULTS: Both the HFD&#x2009;+&#x2009;CBD and HFD&#x2009;+&#x2009;CBD+AT groups showed a significant improvement in beta-cell function, as indicated by a higher HOMA-Beta index compared to the HFD group (p&#x2009;=&#x2009;0.002 and p&#x2009;=&#x2009;0.001, respectively). AT alone (HFD&#x2009;+&#x2009;AT) did not significantly alter HOMA-Beta. In contrast, all intervention groups (HFD&#x2009;+&#x2009;CBD, HFD&#x2009;+&#x2009;AT, and HFD&#x2009;+&#x2009;CBD+AT) demonstrated a significant upregulation in the gene expression of PI3K, AKT, and PDX1 compared to the HFD group (p&#x2009;<&#x2009;0.001 for all). Notably, the combined treatment of CBD and AT (HFD&#x2009;+&#x2009;CBD+AT) produced a synergistic effect, resulting in a greater increase in the expression of all three genes compared to either intervention alone. No significant correlation was found between HOMA-Beta and the gene expression levels within any group (p&#x2009;>&#x2009;0.05). CONCLUSIONS: CBD and AT independently activate the pancreatic PI3K/AKT/PDX1 pathway, with their combination showing synergy. CBD, but not AT alone, improved functional beta-cell mass. This pathway activation represents a key mechanism for protecting beta-cells in obesity.