Cannabidiolic acid mitigates postpartum development of metabolic dysfunction- associated steatotic liver disease in a lean mouse model of gestational diabetes

Background and aims: Gestational diabetes mellitus (GDM) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in mothers postpartum. There has been a growing interest in the potential health benefits of cannabinoids found in Cannabis Sativa, particularly their therapeutic potential in MASLD. The aim of this study was to evaluate whether cannabidiolic acid (CBDA) could ameliorate the development of postpartum MASLD in a lean GDM mouse model.
Materials and methods: Lean GDM was induced in female C57BL/6N mice by high-fat diet and low-dose streptozotocin injections. Control dams received either high-fat (HF) or low-fat (LF) diets. The effect of a 6-week CBDA or vehicle treatment post-weaning on glucose homeostasis and MASLD development was assessed.
Results: The transient hyperglycaemic phenotype observed in GDM dams during pregnancy was followed by hyperglycaemia after lactation. These dams had lower insulin levels and impaired glucose-induced insulin response. CBDA treatment in a postpartum lean GDM mouse model improved glucose tolerance (glucose AUC; GDM Vehicle 2776.4 ± 356.2 vs GDM CBDA 2337.0 ± 315.01, p<0.001) and insulin sensitivity (HOMA-IR; GDM Vehicle 9.71 ± 2.7 vs GDM CBDA 7.3 ± 1.7, p<0.05) without affecting body weight. Hepatic triglyceride levels were increased in vehicle treated GDM dams compared to HF and LF controls, but CBDA supplementation eliminated this difference (GDM Vehicle 108.0 ± 12.3 vs GDM CBDA 65.9 ± 17.8 μmol triglyceride/g liver, p<0.001). CBDA supplementation also decreased metabolic dysfunction-associated steatosis activity scores in the livers of GDM dams (GDM vehicle 4 ± 0.6 vs GDM CBDA 2.9 ± 0.3, p<0.05). Liver gene expression analyses in GDM dams revealed stimulation of pathways linked to lipid oxidation by CBDA.
Conclusion: This study demonstrated that CBDA improved several features of postpartum MASLD following a GDM pregnancy by stimulating pathways linked to hepatic lipid oxidation, simultaneously improving glucose tolerance and insulin sensitivity.