Effect of electroacupuncture at Zusanli reduced Olanzapine‐induced lipid disturbances in mice via potential liver‐brain interaction

Olanzapine-induced weight gain and disruptions in lipid metabolism represent multifactorial processes that compromise treatment adherence in schizophrenia and contribute to substantial clinical challenges. While acupuncture has been reported to promote weight loss, the neural substrates mediating its metabolic effects in olanzapine-induced models remain largely undefined. In this study, we evaluated the efficacy of electroacupuncture (EA) at the Zusanli (ST36) acupoint in ameliorating olanzapine-induced obesity and dyslipidemia, and investigated the underlying liver-brain regulatory mechanisms. We further assessed the effects of EA through Reverse Transcription Polymerase Chain Reaction (RT-PCR), ELISA, and lipidomics analysis. Comprehensive evaluations were conducted using three-dimensional fine behavioral analysis and metabolic cages. Additionally, ultrasound functional imaging (fUS), retrograde tracing with pseudorabies virus 152 (PRV152), and c-Fos mapping techniques were employed to investigate liver-brain interactions. EA at ST36 effectively reduced body weight, reversed Olanzapine-induced adipocyte hypertrophy and hepatocyte damage, and restored disturbances in free fatty acids (FFA) and liver lipid metabolism. These effects also involved the restoration of olanzapine-induced disruptions in respiratory exchange rate (RER) during the dark cycle. We further explored the potential regulatory mechanisms, and we successfully demonstrated that EA stimulation significantly deactivated Agouti-related protein (AGRP)-expressing neurons in the lateral septal nucleus (LS), nucleus accumbens (NAc), and pallidum, suggesting that AGRP+ neurons in these brain regions are involved in the liver-brain interaction during EA treatment. These findings highlight the critical role of metabolism-regulating neurons in the acupuncture-mediated liver-brain axis and provide insights into the mechanisms of information integration from the brain to the liver.