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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 326; no. 2; pp. R100 - R109
• Main Authors: Wilson, Jessica N, Mendez, Dora A, Dhoro, Francis, Shevchenko, Nikolay, Mascal, Mark, Lund, Kyle, Fitzgerald, Robert, DiPatrizio, Nicholas V, Ortiz, Rudy M
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2024
• Subjects: Adiponectin; Adipose tissue; Aged; Animals; Blood Glucose - metabolism; Body mass; Cannabidiol; Cannabidiol - pharmacology; Cannabinoids; Contaminants; Diabetes Mellitus, Type 2 - metabolism; Ghrelin; Glucose; Glucose tolerance; Humans; Insulin; Insulin resistance; Leptin; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - drug therapy; Metabolism; Older people; Proteins; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Skeletal muscle; adiponectin; ghrelin; type II diabetes mellitus; leptin; obesity
• ISSN: 0363-6119; 1522-1490; 1522-1490
• DOI: 10.1152/ajpregu.00125.2022

Cannabidiol (CBD) use has grown exponentially more popular in the last two decades, particularly among older adults (>55 yr), though very little is known about the effects of CBD use during age-associated metabolic dysfunction. In addition, 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-wk-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered 200 mg H4CBD/kg by oral gavage for 4 wk. 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 wk of treatment. When compared with 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 (AUC ) by 29% ( < 0.001) and insulin resistance index (IRI) by 25% ( < 0.05) compared with 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%; < 0.05). H4CBD reduced circulating adiponectin (40%; < 0.05) and leptin (47%; < 0.05) and increased ghrelin (75%; < 0.01) compared with 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. Cannabis product use has grown in the last two decades despite the lack of research on Cannabidiol (CBD)-mediated effects on metabolism. Here, we provide seminal data on CBD effects during age-associated metabolic dysfunction. We gave 41-wk-old OLETF rats 200 mg H4CBD/kg by mouth for 4 wk and noted a high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling, and these effects are likely a benefit of loss of visceral adiposity.