Synthetic Cannabidiol Reduced Body Mass and Visceral Adiposity but Not Blood Pressure in Rats With Advanced Metabolic Syndrome

Abstract

Very little is known about the effects of CBD on age‐associated cardiovascular and metabolic dysfunction. The prevalence of metabolic syndrome (MetS) is 54.9% among people ≥60 years of age, which increases the risk of the development of associated pathologies like cardiovascular disease and type II diabetes. Additionally, synthetic CBD alternatives offer a chemically pure product, which is free of plant‐associated contaminants. To assess the effects of the synthetic CBD, H4CBD, on advanced metabolic dysfunction, a cohort of 41‐week‐old lean strain Long‐Evans Tokushima Otsuka (LETO) rats (n=8) and MetS strain Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were administered sesame oil vehicle (n=8) or 200 mg H4CBD/kg (OLETF n=8) by oral gavage for 4 weeks. Animals were fed standard chow ad libitum and monitored for systolic blood pressure (SBP), activity, body mass (BM), food intake and urinary excretion. After 4 weeks, H4CBD tended to increase activity scores in OLETF (p=0.099) and reduced BM to control levels within the first week. Retroperitoneal and epidydimal fat masses were reduced 25% compared to untreated OLETF. However, the H4CBD‐induced loss of visceral adiposity was not associated with reduced arterial blood pressure. Clinical indicator for muscle wasting, urinary 3‐methylhistidine (3MH), ratioed to urinary creatinine (Cr) (3MH/Cr), suggested the primary mass lost was adipose. An oral glucose tolerance test (oGTT) was performed after 4 weeks of treatment. Glucose response was reduced (AUCglucose) 29% (p<0.001) by H4CBD treatment compared to control and reduced insulin resistance index (IRI) by 25% (p<0.05). However, H4CBD‐induced improvements to glucose tolerance did not associate with reduced basal blood glucose or plasma insulin, despite compensatory increases in insulin receptor (IR) protein expression (54%; p<0.05) and membrane‐bound glucose transporter protein 4 (GLUT4) protein expression (41.5%). The results suggest that a chronic, high dose of CBD may improve glucose tolerance, independent of insulin signaling, without caloric restriction via increased activity. H4CBD reduced plasma triglycerides by 45% (p<0.05) but not plasma NEFA suggesting that de novo TG synthesis was reduced. The results suggest that a chronic, high dose of CBD may drive fat loss via increased activity and reduced TG synthesis, but the mass loss was not sufficient to correct the associated hypertension or impaired substrate metabolism common in MetS for this duration of treatment and advanced stage of dysregulated metabolism.