The effect and mechanisms of risperidone and voluntary exercise intervention on hepatic lipid metabolism in juvenile female rats

Objectives Risperidone is a commonly used antipsychotic drug in juveniles, but with serious metabolic side-effects. Previous studies found that exercise reduced plasma triglyceride level and adipose accumulation caused by risperidone. This study elucidated the underlying mechanisms. Methods Female juvenile rats were randomly allocated into Vehicle + Sedentary, Risperidone (0.9mg/kg; twice per day) + Sedentary, Vehicle + Exercise (3-hour voluntary access to a running wheel/day), and Risperidone + Exercise groups (n = 8/group). After 4-week treatment, the liver was harvested for subsequent examination. Results (1) Lipogenesis: Protein levels of FAS and USF1 were raised in the risperidone-treated sedentary group, which was decreased by exercise. The pAMPK/AMPK ratio was upregulated by exercise. (2) Lipid uptake/storage: Risperidone-induced upregulations of PPARγ and CD36 were downregulated by exercise. FSP27 expression was decreased by exercise. (3) Lipolysis/β-oxidation: Hepatic protein levels of ATGL and HSL in the Risperidone + Exercise group were larger than Risperidone + Sedentary group. Reduced PGC1α expression was found in the risperidone-only group, which was reversed by exercise. Conclusion Risperidone enhanced fatty acid synthesis via the hepatic USF1/FAS signaling pathway and to augment fatty acid uptake through the PPARγ/CD36 pathway, while simultaneously diminishing β-oxidation by down-regulating hepatic PGC1α expression. Conversely, voluntary exercise intervention counteracted these effects, thereby ameliorating the lipid imbalances induced by risperidone.