Avera Institute for Human Genetics, Avera McKennan Hospital & University Health Center, Sioux Falls, South Dakota, United States of America; Department of Psychiatry, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, United States of America.
Department of Veterinary and Biomedical Sciences, College of Agriculture & Biological Sciences, South Dakota State University, Brookings, South Dakota, United States of America.
PLoS One. 2014 Mar 25;9(3):e93310. doi: 10.1371/journal.pone.0093310. eCollection 2014.
Olanzapine is a first line medication for the treatment of schizophrenia, but it is also one of the atypical antipsychotics carrying the highest risk of weight gain. Metformin was reported to produce significant attenuation of antipsychotic-induced weight gain in patients, while the study of preventing olanzapine-induced weight gain in an animal model is absent. Berberine, an herbal alkaloid, was shown in our previous studies to prevent fat accumulation in vitro and in vivo. Utilizing a well-replicated rat model of olanzapine-induced weight gain, here we demonstrated that two weeks of metformin or berberine treatment significantly prevented the olanzapine-induced weight gain and white fat accumulation. Neither metformin nor berberine treatment demonstrated a significant inhibition of olanzapine-increased food intake. But interestingly, a significant loss of brown adipose tissue caused by olanzapine treatment was prevented by the addition of metformin or berberine. Our gene expression analysis also demonstrated that the weight gain prevention efficacy of metformin or berberine treatment was associated with changes in the expression of multiple key genes controlling energy expenditure. This study not only demonstrates a significant preventive efficacy of metformin and berberine treatment on olanzapine-induced weight gain in rats, but also suggests a potential mechanism of action for preventing olanzapine-reduced energy expenditure.
奥氮平是治疗精神分裂症的一线药物，但它也是导致体重增加风险最高的非典型抗精神病药之一。二甲双胍已被报道能显著减轻患者因使用抗精神病药物而导致的体重增加，而在动物模型中预防奥氮平引起的体重增加的研究则尚未进行。小檗碱是一种植物生物碱，我们之前的研究表明它可以预防体外和体内脂肪堆积。利用奥氮平诱导体重增加的复制良好的大鼠模型，我们在这里证明，二甲双胍或小檗碱治疗两周可显著预防奥氮平引起的体重增加和白色脂肪堆积。二甲双胍或小檗碱治疗均未显示出对奥氮平增加的食物摄入有显著抑制作用。但有趣的是，奥氮平治疗引起的棕色脂肪组织大量损失被添加的二甲双胍或小檗碱所预防。我们的基因表达分析还表明，二甲双胍或小檗碱治疗的体重增加预防效果与控制能量消耗的多个关键基因表达的变化有关。这项研究不仅证明了二甲双胍和小檗碱治疗对大鼠奥氮平诱导的体重增加有显著的预防作用，而且还提示了预防奥氮平降低能量消耗的潜在作用机制。
