Pseudocannabinoid H4CBD enhances lipid catabolism to reduce visceral adiposity and large adipocyte size in advanced metabolic syndrome

Background Metabolic Syndrome (MetS) is a precursor for cardiovascular disease (CVD) and type 2 diabetes (T2D) and has a prevalence of 55% among people ≥ 60 years of age in the US. Cannabidiol (CBD) use has grown more popular in the last two decades, particularly amongst adults > 55 years of age. Synthetic analogues of CBD have generated great interest because they can offer safer, chemically pure products with no abuse potential and no regulatory barriers. However, the effects of chronic cannabinoid use during age-associated cardiometabolic dysfunction have not been examined. Methods To assess the effects of H4CBD, a synthetic analogue of CBD, on advanced MetS, 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 lean, strain-control Long-Evans Tokushima Otsuka (LETO) rats. Results Body mass (BM) was reduced 22% in H4CBD group compared to OLETF and was similar to LETO levels within the first week but did not reverse the diabetic phenotype of the aged OLETF. H4CBD also reduced visceral fat mass (FM; 41%) and nearly ablated large adipocyte (> 100µm) abundance compared to OLETF. Plasma triglycerides were more than doubled in OLETF compared to LETO, and H4CBD normalized the levels. Urinary 3-methylhistidine (3-MH) to creatinine ratio tended to be higher (77%; p = 0.07) in H4CBD suggesting that some lean tissue was lost along with FM, which contributed to the reduction in BM. Conclusions Chronic H4CBD treatment increased lipid catabolism resulting in increased FM loss, although some lean mass loss was also observed. These results suggest that synthetic cannabinoids have potential for advanced-age obesity management during severe metabolic dysfunction, even with consideration of possible cachexic effects.