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Characterising the Phenotype and Impact of Adipose in Idiopathic Intracranial Hypertension

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Characterising the Phenotype and Impact of Adipose in Idiopathic Intracranial Hypertension Characterising the Phenotype and Impact of Adipose in Idiopathic Intracranial Hypertension By Connar Stanley James Westgate A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Institute of Metabolism and Systems Research College of Medical and Dental Sciences University of Birmingham April 2019 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Idiopathic intracranial hypertension (IIH) is a rare disease that primarily affects obese women of reproductive age, characterised by raised intracranial pressure (ICP) and papilloedema that drives chronic debilitating headache and visual loss. The aetiology of IIH is uncertain, however it is clear that weight loss is therapeutic and reduces ICP, headache, and visual morbidity. Novel data has highlighted that female IIH patients have an androgen excess phenotype. However the role of adipose tissue and androgens in the pathogenesis of IIH remains unclear. Utilising RNA-sequencing, NMR-based metabolomics and secretomic techniques, it has been identified that ex vivo subcutaneous adipose tissue from female IIH patients has features of glucocorticoid excess including increased lipolysis, ribosomal subunit depletion and a preference for lipid synthesis, driven by intra-adipose cortisol accumulation. Moreover, this phenotype is driving hyperleptinaemia in IIH patients. Additionally, a novel in vitro Na+/K+ ATPase activity assay was developed, which demonstrated that testosterone increases Na+/K+ ATPase activity, suggesting capacity to increase ICP. Together, these data highlight that adipose tissue in IIH has characteristics of glucocorticoid excess, contributing to a specific metabolic phenotype and that testosterone could be driving raised intracranial pressure, highlighting routes for the development of novel therapeutics and treatments for IIH. i | P a g e Acknowledgments A PhD is a journey, as such I wish to thank those who have joined me on this journey. Firstly I want to convey my heart felt gratitude to my supervisors, firstly Alex Sinclair for her guidance and mentorship which has helped me grow as a scientist, and for her help in keeping me motivated when things were not going according to plan. Secondly, to Gareth Lavery, for his calming influence, experience and oversight in guiding this work. I also wish to thank members past and present of the metabolic neurology group who have helped enrich my PhD. In particular, I wish to thank Hannah Botfield who taught me pretty much everything in the lab and for being an excellent mentor. I also wish to thank James Mitchell for his critical mind and our stimulating conversations about science and beyond. I also which to thank members of the IMSR for their collective scientific companionship, I however wish to specifically thank David Hodson and Nick Fine for the their assistance with live cell microscopy, Dean Larner for conferring his sage wisdom of histology and Mick O’Reilly for his advice on all things adipose and androgens. I wish to thank the lunchtime group, especially the ‘Coup’ team of Haydn, Rob, Nick and ρ-dog who helped keep me sane with the immortal words ‘3 coins as the duke’. I want to thank the Danish Headache Centre for being welcoming during my time there. I also want to thank the bariatric team at Heartlands hospital, especially Mr Singhal and Mr Super for their exemplary efforts in recruiting ii | P a g e patients and providing me with precious tissue samples. Without these, my thesis would look very different. Thanks with all my heart go to my family for their continuous and unwavering support during my PhD, especially during my write-up. You have always believed in me and encouraged me to succeed. To Ola, who has been at my side during the highs and lows of my PhD, I want to thank you for your continuous support, encouragement and patience. iii | P a g e For Daniel, Elliott and Lillyanna iv | P a g e Declaration I confirm that the data presented in this thesis is my own and that I have been involved in the design, conduct, data analysis and the preparation of the thesis. The following aspects of this thesis were undertaken as part of collaboration: 1) Mark Walsh and Daniel Hebenstreit of the University of Warwick and Ildem Akerman and Gabrielle Smith of the University of Birmingham carried out bioinformatic analysis of RNA sequencing data. 2) Christian Ludwig acquired NMR spectra within the study. 3) William Scotton and Hannah Botfield carried out surgeries on a portion of the animals in the in vivo ICP experiments. I undertook all other experiments and statistical analyses within this thesis v | P a g e Publications and presentations Peer reviewed papers directly from this doctoral research O’Reilly MW*, Westgate CSJ*, Hornby C*, Botfield HF*, Taylor AE, Markey K, Mitchell JL, Scotton WJ, Mollan SP, Yiangou A, Jenkinson C, Gilligan LC, Sherlock M, Gibney J, Tomlinson JW, Hodson DJ, Arlt W and Sinclair A. A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics. Journal of Clinical Investigation Impact, 2019; 4(6): e125348. Portions of this paper appear in chapters 5 and 6. Scotton WJ, Botfield HF, Westgate CSJ, Mitchell JL, Yiangou A, Uldall MS, Jensen RH, Sinclair A. Topiramate is more effective than acetazolamide at lowering intracranial pressure. Cephalalgia, 2018. Portions of this paper are in chapter 5. Botfield HF, Uldall M, Westgate CSJ, Mitchell JL, Hagen SM, Gonzalez AM, Hodson DJ, Jensen RH, Sinclair A. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus. Science Translational Medicine, 2017; 9(404), eaan0972. None of this work appears in this thesis. Hornby C, Botfield HF, O’Reilly MW, Westgate CSJ, Mitchell JL, Mollan SP, Manolopoulos K, Tomlinson J, Sinclair A. Evaluating the Fat Distribution in Idiopathic Intracranial Hypertension Using Dual-Energy X- ray Absorptiometry Scanning. Neuro-Ophthalmology, 2018; 42 (2),99- 104. None of this work appears in this thesis. vi | P a g e Conference abstracts and talks ‘Subcutaneous adipose tissue from patients with idiopathic intracranial hypertension displays distinct metabolic features’ at Society for Endocrinology BES meeting , Glasgow, November 2018 ‘Subcutaneous adipose tissue from patients with idiopathic intracranial hypertension displays unique transcriptomic and metabolic features’ at Migraine Trust international symposium, London, September 2018 ‘Evaluating the role of testosterone in cerebrospinal fluid secretion’ at the Society for Endocrinology BES meeting, Harrogate, November 2017 ‘Characterising the role of androgens in cerebrospinal fluid secretion’ Invited talk at the UK CSF day, Birmingham, September 2017 ‘Developing a cerebrospinal fluid secretion assay using a genetically encoded biosensor to evaluate therapeutic and pathogenic molecules in idiopathic intracranial hypertension’ at International Headache Society congress, Vancouver September 2017 (Poster of distinction) vii | P a g e Table of Contents Abstract ................................................................................................................ i Acknowledgments ............................................................................................... ii Declaration .......................................................................................................... v Publications and presentations .......................................................................... vi Peer reviewed papers directly from this doctoral research ................................ vi Conference abstracts and talks ......................................................................... vii Table of Contents ............................................................................................. viii List of Figures ................................................................................................... xv List of tables .................................................................................................... xviii List of abbreviations ......................................................................................... xix Chapter 1 General Introduction ........................................................................... 1 1.1 Idiopathic intracranial Hypertension .............................................................. 2 1.1.1 Idiopathic intracranial hypertension diagnosis ........................................ 3 1.1.2 Epidemiology of idiopathic intracranial hypertension .............................. 4 1.1.3 Idiopathic intracranial pressure and co-morbidities ................................. 4 1.1.3.1 Headache in IIH ................................................................................ 4 1.1.3.2 Visual loss in IIH ............................................................................... 5 1.1.3.3 IIH as a metabolic syndrome ............................................................ 5 1.1.3.4 IIH
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