Department of Pharmacology and Toxicology (R.H.S., J.D.J., V.L.M., J.I.B., G.E.A.), and Department of Medicine (K.C.F.), Health Sciences Center, and Department of Chemistry (X.S., X.Y., X.Z.), University of Louisville, Louisville, Kentucky.
J Pharmacol Exp Ther. 2013 Oct;347(1):126-35. doi: 10.1124/jpet.113.207621. Epub 2013 Aug 7.
Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug.
奥氮平（OLZ）是一种有效的精神分裂症和其他疾病的治疗药物，但会导致体重增加和代谢综合征。迄今为止，大多数研究都集中在 OLZ 对中枢神经系统介导体重的潜在影响上；然而，肝脏或其他关键代谢器官的外周变化也可能在 OLZ 的全身作用中发挥作用。因此，本研究旨在研究 OLZ 在 OLZ 暴露的小鼠模型中对肝脏代谢的影响。雌性 C57Bl/6J 小鼠通过渗透微型泵每天皮下给予 OLZ（8mg/kg）或载体 28 天。牺牲时取肝和血浆进行生化分析和全面二维气相色谱与飞行时间质谱代谢组学分析。OLZ 增加了体重、脂肪垫质量和肝体比，而食物消耗没有相应增加，这表明 OLZ 改变了能量消耗。表达和生化分析表明，OLZ 诱导无氧糖酵解并导致假性禁食状态，耗尽了肝糖原储备。通过 Seahorse 分析，OLZ 在培养的 HepG2 细胞中也产生了类似的作用。代谢组学分析表明，OLZ 增加了肝脏中可以通过 mTOR 途径改变代谢的氨基酸浓度；事实上，OLZ 强烈增加了肝 mTOR 信号。有趣的是，OLZ 同时激活了 AMP 激活的蛋白激酶（AMPK）信号。总之，这些数据表明，OLZ 在肝脏中引起的葡萄糖和脂质代谢紊乱至少部分是通过同时激活分解代谢（AMPK）和合成代谢（哺乳动物雷帕霉素靶蛋白）途径介导的，这为该药物的代谢副作用提供了新的见解。
