University of Wollongong Research Online University of Wollongong Thesis Collection 1954-2016 University of Wollongong Thesis Collections 2014 The time-dependent role of brain histaminergic system and associated AMPK signaling in olanzapine-induced obesity Meng He University of Wollongong Follow this and additional works at: https://ro.uow.edu.au/theses University of Wollongong Copyright Warning You may print or download ONE copy of this document for the purpose of your own research or study. The University does not authorise you to copy, communicate or otherwise make available electronically to any other person any copyright material contained on this site. You are reminded of the following: This work is copyright. Apart from any use permitted under the Copyright Act 1968, no part of this work may be reproduced by any process, nor may any other exclusive right be exercised, without the permission of the author. Copyright owners are entitled to take legal action against persons who infringe their copyright. A reproduction of material that is protected by copyright may be a copyright infringement. A court may impose penalties and award damages in relation to offences and infringements relating to copyright material. Higher penalties may apply, and higher damages may be awarded, for offences and infringements involving the conversion of material into digital or electronic form. Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong. Recommended Citation He, Meng, The time-dependent role of brain histaminergic system and associated AMPK signaling in olanzapine-induced obesity, Doctor of Philosophy thesis, School of Medicine, University of Wollongong, 2014. https://ro.uow.edu.au/theses/4626 Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] THE TIME-DEPENDENT ROLE OF BRAIN HISTAMINERGIC SYSTEM AND ASSOCIATED AMPK SIGNALING IN OLANZAPINE-INDUCED OBESITY A thesis submitted in fulfilment of the requirements for the award of the degree DOCTOR OF PHILOSOPHY From School of Medicine University of Wollongong By Meng He 2014 1 CERTIFICATION I, Meng He, declare that this thesis, submitted in fulfilment of the requirements for the award of Doctor of Philosophy, in the School of Medicine, University of Wollongong, is entirely my own work unless otherwise referenced or acknowledged. This manuscript has not been submitted for qualification at any other academic institution. Meng He June 2014 ii Statements In accordance with the University of Wollongong thesis committee ‗Guidelines for the Preparation and Submission of Thesis‘, this PhD thesis is presented in ‗traditional monograph style‘. I declare that I am the designer of the experiments, have carried out the experimental procedures, data statistical analysis and manuscript preparation. Meng He June 2014 iii Acknowledgments I would like to thank the School of Medicine, Faculty of Science, Medicine and Health, and the Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong (UOW), as well as the China Scholarship Council – University of Wollongong Joint Postgraduate Scholarship for the funding and support, and travel grants. I would like to express my sincere thanks to my supervisors Professor Xu-Feng Huang and Associate Professor Chao Deng for their patience, motivation, support and encouragement during my PhD studies. I thank them for their time and guidance to allow me to build my knowledge, solve the problems I met during my studies, improve my academic writing, and prepare published papers. Their advice was priceless to me and will be of great assistance in my future research career. I thank Professor Changhua Hu, Ms Hongqin Wang, Mr Qingsheng Zhang, Mr Martin Engel, Ms Linda Cohen, Dr Katrina Green, Ms Jiamei Lian, Ms Yizhen Wu, Ms Diane Walton and other colleagues at the Centre for Translational Neuroscience for their help in technical assistance, statistical analysis, preparation and editorial reading of my manuscripts and the critical proofreading of my final PhD thesis. I thank Dr Tracey Maddocks for her help and support during my animal experiments. A special thanks to my family. Words cannot express how grateful I am to my parents and sister for all their sacrifice and support during this period of study. Thanks to my husband, Cheng Chen, for his encouragement and help during my thesis writing and for taking care of me. Finally thanks to all my friends for their help during my studies. iv PUBLICATIONS The following publications and presentations have arisen directly from work contained in this thesis Publications in Refereed Journals: He, M., Deng, C. and Huang, X.F., 2013. The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain. CNS Drugs 27, 423-434. He, M., Zhang Q., Deng, C., Wang H.Q., Lian J. and Huang, X.F., 2014. Hypothalamic histamine H1 receptor-AMPK signaling time-dependently mediates olanzapine-induced hyperphagia and weight gain in female rats. Psychoneuroendocrinology 42, 153-164 He, M., Zhang Q., Deng, C., Wang H.Q. and Huang, X.F., 2014 Olanzapine-activated AMP-activated protein kinase signaling in the dorsal vagal complex is attenuated by histamine H1 receptor agonist in female rats. Endocrinology 155 (12):4895-4904. Conference proceedings: He, M., Zhang, Q., Wang, H.Q., Lian, J., Deng, C. and Huang, X.F. (2012). Olanzapine treatment and time-dependent changes of hypothalamic AMPK- ACC-CPT1 signaling, food intake and body weight in rats. Proceedings of the v Australian Neuroscience Society 32nd Annual Meeting, ANS, Australia, 148-148. He, M., Zhang, Q., Wang, H.Q., Deng, C. and Huang, X.F. (2013). Central administration of histamine H1 receptor agonist, FMPH, blocks olanzapine-induced activation of AMPK-CPT1 signaling in the dorsal vagal complex in rats. Proceedings of the Australian Neuroscience Society 33rd Annual Meeting, ANS, Australia, 120- 120. He, M., Wang, H.Q., Han, M., Deng, C. and Huang X.F. (2014). Acute olanzapine treatment blocks the histamine H1 receptors leading to activated AMPK signaling in the hypothalamic arcuate nucleus and brainstem dorsal vagal complex. 34th Australian Neuroscience Society Annual meeting; 2014 Jan 28- Jan 31; Adelaide Other publications and conference proceedings: Zhang, Q., He, M., Deng, C., Wang, H., Lian, J. and Huang, X.F, 2014. Hypothalamic ghrelin signaling mediates olanzapine-induced hyperphagia and weight gain in female rats. The international journal of neuropsychopharmacology 17, 807-18. Zhang Q, Lian J, He M, Deng C, Wang H. and Huang XF. 2014. Olanzapine reduced brown adipose tissue thermogenesis and locomotor activity in female rats. Progress in neuro-psychopharmacology & biological psychiatry 51, 172-80. vi Zhang Q., He M., Deng C., Wang H. and Huang X.F. Time-related effects of olanzapine on elevation of macrophage infiltration and pro-inflammation cytokine expressions in female rats. Journal of psychopharmacology; 28(12):1161-9. Zhang, Q., He, M., Wang, H., Lian, J., Deng, C. and Huang, X. F. (2013). Brown Adipose Tissue Thermogenesis Is Time-Dependently Downregulated by Olanzapine in Rats. Proceedings of the 31st Annual Scientific Meeting of the Obesity Society, November 2013, Atlanta, GA, USA: T-715-P. Zhang, Q., He, M., Wang, H., Lian, J., Deng, C. and Huang, X. F. (2013). Time- dependent ghrelinergic signaling and hyperphagia induced by olanzapine. Proceedings of the Australian Neuroscience Society 33rd Annual Meeting, ANS, Australia: 48-48. Zhang, Q., He, M., Wang, H., Lian, J., Deng, C. and Huang, X. F. (2012). Time- dependant alterations of hypothalamic energy regulatory network by olanzapine in rats. Proceedings of the Australian Neuroscience Society 32nd Annual Meeting, ANS, Australia: 150-150. vii ABSTRACT Treatment with second generation antipsychotics (SGAs), particularly clozapine and olanzapine, is associated with severe obesity side-effects. Histamine H1 receptor (H1R) antagonism has been identified as a main cause of SGA-induced obesity, but its molecular mechanisms remain unclear. The hypothalamus and brainstem dorsal vagal complex (DVC) are well-documented in the regulation of food intake and body weight. Using an established olanzapine-induced obesity rat model, this study investigated the role of brain histaminergic system and its associated AMP-activated protein kinase (AMPK) signaling in the hypothalamus and DVC at different stages (early acceleration, middle new equilibrium, and late heavy weight maintenance) of olanzapine-induced obesity. Firstly, I studied the effect of olanzapine on key components of the histaminergic system, histidine decarboxylase (HDC), H1R and H3R, in the brain at different stages of olanzapine-induced obesity. Female rats were treated orally with olanzapine (1 mg/kg, tid, 8-hourly) for 8, 16 and 36 days to represent the three stages of olanzapine- induced obesity. At the early stage, olanzapine increased the hypothalamic HDC mRNA expression and H1R binding in the arcuate nucleus (Arc) and ventromedial hypothalamus (VMH). HDC mRNA and Arc H1R binding positively correlated with feeding efficiency and weight gain, contributing to hyperphagia and rapid weight gain. At the middle and late stage, olanzapine increased H1R binding in the Arc, VMH and DVC. Changes in H1R binding positively correlated with weight gain indicated their importance in chronic olanzapine-induced obesity. Olanzapine