title: Olanzapine reduced brown adipose tissue thermogenesis and locomotor activity in female rats.
abstract: 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.
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia; Illawarra Health and Medical Research Institute, Wollongong, 2522 NSW, Australia.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia; Illawarra Health and Medical Research Institute, Wollongong, 2522 NSW, Australia.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lian
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia; Illawarra Health and Medical Research Institute, Wollongong, 2522 NSW, Australia.
authors.forename: Meng
authors.initials: M
authors.lastname: He
authors.affiliation: 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia; Illawarra Health and Medical Research Institute, Wollongong, 2522 NSW, Australia.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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. Electronic address: xhuang@uowmail.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D015331:Cohort Studies; D015536:Down-Regulation / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D000077152:Olanzapine; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D022722:Thermogenesis / Q000187:drug effects*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D014150:Antipsychotic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D001569:Benzodiazepines; D014446:Tyrosine 3-Monooxygenase; D000077152:Olanzapine
keywords: Antipsychotics; Brown adipose tissue; PGC-1α; Thermogenesis; Weight gain