Zhang Qingsheng, Lian Jiamei, He Meng, Deng Chao, Wang Hongqin, Huang Xu-Feng
Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia; Illawarra Health and Medical Research Institute, Wollongong, 2522 NSW, Australia.
Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia; Illawarra Health and Medical Research Institute, Wollongong, 2522 NSW, Australia; Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010 NSW, Australia.
Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jun 3;51:172-80. doi: 10.1016/j.pnpbp.2014.02.003. Epub 2014 Feb 16.
Excessive weight gain has been identified as a serious metabolic side-effect of second-generation antipsychotics (SGAs), including olanzapine. While hyperphagia has been suggested to be the main contributor for this side-effect in the short term, reduced energy expenditure, in particular thermogenesis and locomotor activity, has been considered to contribute to the maintenance of heavy weight under long-term SGA treatments. Recent studies have identified metabolically active brown adipose tissues (BAT) in adult humans, suggesting potential clinical significance for the involvement of BAT thermogenesis in SGA-induced weight gain. However, to date there has been little research elucidating the central neuronal pathways affecting BAT thermogenesis or the morphological changes of the BAT. The present study aimed to investigate the role of BAT thermogenesis and locomotor activity in olanzapine-induced weight gain during the prolonged time courses of olanzapine treatment in an established female rat model. Although short- to mid-term olanzapine treatment had no effect on BAT temperature, we observed that long-term olanzapine treatment (from day 18 to 34) induced a significant reduction in BAT temperature, with an acute effect being observed between 45 and 150 min post-treatment in the long-term cohort. Additionally, in the long-term olanzapine group, the reduced BAT temperature was accompanied by decreased UCP1 and PGC-1α expressions in the BAT. Moreover, TH mRNA expressions in both hypothalamus and brainstem were also downregulated after mid- to long-term olanzapine treatment. Further, olanzapine led to reduced percentage of brown adipocytes in BAT during mid- to long-term treatments. Finally, locomotor activity was reduced throughout the three treatment cohorts. In summary, our results suggest that the reduction of BAT thermogenesis plays an important role during the long-term of olanzapine-induced weight gain, which was accompanied by an earlier onset of BAT adipocyte morphological changes and biochemical changes in the hypothalamus and the brainstem, while locomotor activity contributes to the entire olanzapine treatment courses.
体重过度增加已被确认为包括奥氮平在内的第二代抗精神病药物（SGA）的严重代谢副作用。虽然短期内暴饮暴食被认为是这种副作用的主要原因，但能量消耗减少，特别是产热和运动活动减少，被认为在长期SGA治疗中导致体重增加。最近的研究已经在成年人体内发现了具有代谢活性的棕色脂肪组织（BAT），这表明BAT产热参与SGA诱导的体重增加具有潜在的临床意义。然而，迄今为止，很少有研究阐明影响BAT产热的中枢神经通路或BAT的形态变化。本研究旨在探讨在已建立的雌性大鼠模型中，在奥氮平治疗的延长时间过程中，BAT产热和运动活动在奥氮平诱导的体重增加中的作用。虽然短期至中期奥氮平治疗对BAT温度没有影响，但我们观察到长期奥氮平治疗（从第18天到34天）导致BAT温度显著降低，在长期组中，治疗后45至150分钟观察到急性效应。此外，在长期奥氮平组中，BAT温度降低伴随着BAT中UCP1和PGC-1α表达的降低。此外，中长期奥氮平治疗后，下丘脑和脑干中的TH mRNA表达也下调。此外，在中长期治疗期间，奥氮平导致BAT中棕色脂肪细胞的百分比降低。最后，在三个治疗组中运动活动均降低。总之，我们的结果表明，BAT产热的降低在长期奥氮平诱导的体重增加中起重要作用，同时伴有BAT脂肪细胞形态变化以及下丘脑和脑干生化变化的更早发生，而运动活动在整个奥氮平治疗过程中都有影响。
