Pseudocannabinoid H4CBD improves glucose response during advanced metabolic syndrome in OLETF rats independent of increase in insulin signaling proteins

Abstract

Cannabidiol (CBD) use has grown exponentially more popular in the last two decades, particularly amongst older adults (>55 years), though very little is known about the effects of CBD use during age-associated metabolic dysfunction. Additionally, synthetic analogues of CBD have generated great interest because they can offer a chemically pure product, which is free of plant-associated contaminants. To assess the effects of a synthetic analogue of CBD (H4CBD) on advanced metabolic dysfunction, a cohort of 41-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered 200 mg H4CBD/kg by oral gavage for 4 weeks. Animals were fed ad libitum and monitored alongside vehicle-treated OLETF and Long-Evans Tokushima Otsuka (LETO) rats, the lean-strain controls. An oral glucose tolerance test (oGTT) was performed after 4 weeks of treatment. When compared to vehicle-treated OLETF rats, H4CBD decreased body mass (BM) by 15%, which was attributed to a significant loss in abdominal fat. H4CBD reduced glucose response (AUCglucose) by 29% (p<0.001) and insulin resistance index (IRI) by 25% (p<0.05) compared to OLETF rats. However, H4CBD did not statically reduce fasting blood glucose or plasma insulin, despite compensatory increases in skeletal muscle native insulin receptor (IR) protein expression (54%; p<0.05). H4CBD reduced circulating adiponectin (40%; p<0.05) and leptin (47%; p<0.05) and increased ghrelin (75%; p<0.01) compared to OLETF. Taken together, a chronic, high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling and these effects are likely a benefit of the profound loss of visceral adiposity.