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The Interaction of Obesity and Age and Their Effect on Adipose Tissue Metabolism in the Mouse

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The Interaction of Obesity and Age and Their Effect on Adipose Tissue Metabolism in the Mouse The Interaction of Obesity and Age and their effect on Adipose Tissue Metabolism in the Mouse A dissertation submitted for the degree of Doctor of Philosophy at the University of Cambridge Ke-di Liu King’s College Declaration This thesis is a summary of research conducted in the Department of Biochemistry, University of Cambridge, between October 2013 and September 2017. This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration, except where specially indicated in the text. None of the research described, in its entirety or in part, has been submitted for a degree, diploma or other qualification at any other University. This thesis does not exceed 60,000 words. Abstract Numerous studies have investigated how bulk lipid metabolism is influenced in obesity and in particular how the composition of triglycerides found in the cytosol change with increased adipocyte expansion. However, in part reflecting the analytical challenge the composition of cell membranes, and in particular glycerophospholipids, an important membrane component, have been seldom investigated. Cell membrane components contribute to a variety of cellular processes including maintaining organelle functionality, providing an optimized environment for numerous proteins and providing important pools for metabolites, such as choline for one- carbon metabolism and S-adenosylmethionine for DNA methylation. Here, I have conducted a comprehensive lipidomic and transcriptomic study of white adipose tissue in mice that become obese either through genetic modification (ob/ob genotype), diet (high-fat diet) or a combination of the two across the life course. Specifically, I demonstrated that the changes in triglyceride metabolism that dominate the overall lipid composition of white adipose tissue were distinct from the compositional changes of glycerophospholipids. These latter lipids became more unsaturated to maintain the fluidity and normal function of the membrane in the initiation of obesity but then turned saturated after long-term administration of HFD and aging. This suggests that while triglycerides within the adipose tissue may be a relatively inert store of lipids, the compositional changes occur in cell membranes with more far-reaching functional consequences in both obesity and aging. The two-phase change of phospholipids can be correlated well with transcriptional and one-carbon metabolic changes within the adipocytes. The transcriptomic study demonstrated that the lipid metabolic pathways regulated by the peroxisome, AMPK, insulin and PPARγ signaling were activated in the initiation of obesity but inhibited in the adipose tissue of old ob/ob mice along with up-regulated inflammation pathways. The brown and white adipose tissue of PPARα-knock-out mice were also studied by lipidomic tools to get a deeper understanding of the effect of the peroxisome and PPAR system on adipose tissue and lipid metabolism during obesity. Most of the lipids were increased and became more saturated and shorter in adipose tissues of PPARα null mice, which is in good accordance with the results of the former animal study. In conclusion, my work using different rodent models and multi-omics techniques demonstrated a protective metabolic mechanism activated in the initiation but impaired at the end of the processes of obesity and aging, which could be an explanation of the similarity of obesity and aging in terms of high incidence of the metabolic syndrome and related diseases. Publication Hanli Xu, Shaowei Wang, Lin-Lin Ma, Shuai Huang, Lin Liang, Qian Liu, Yang-Yang Liu, Ke-Di Liu, Ze-Min Tan, Hao Ban, Yongtao Guan, and Zuhong Lu (2017) Informative Priors on Fetal Fraction Increase Power of The Noninvasive Prenatal Screen. Genetics in Medicine, accepted. Presentation The Interaction of Diet with Epigenetic Modifications in Adipose Tissue Metabolism. Poster presented in 42nd Adipose Tissue Discussion Group (ATDG) Meeting, 14th December 2015, University of Westminster, London. Acknowledgments Pursuing studies as a Ph.D. student in the past four years in Cambridge has been such a wonderful, unforgettable, and sometimes overwhelming experience. I own a great debt of thanks to many people for the support they have provided. First and foremost, I wish to express my deep gratitude to my supervisor, Prof. Jules Griffin, the best supervisor I could dream of. It was his professional guidance, unwavering support, and genuine caring and faith in me that had kept me working every time I wanted to give up during the course of this work, without whom this Ph.D. thesis would never have been written. I am also deeply grateful to Dr. Andrew Murray for providing the animals and his kind help with animal work. I’d like to give special thanks to my colleagues Xinzhu Wang, Yajing Chu, and Helena Matthews, who laid the groundwork for the obesity and aging animal study. And many thanks to Lee Roberts, Animesh Acharjee, James West, Steve Murffit, Zsuzsanna Ament, Helene Mobbs, Ben McNally and all the past and present members of the Griffin group, all of whom have offered their technical expertise and advice, gave generous amount of their time with me and have always been a pleasure to work with. I am very grateful to all my friends met in Cambridge. Thank you for your friendship, support, and being encouraging making my time at Cambridge special. It is due to you that I have so enjoyed my time in Cambridge. I would always recall our memorable moments. Special thanks to my parents for their enduring support and encouraging me to pursue enlightenment and precious knowledge, to my sister, who passed her genuine caring over the telephone in the early days of my overseas student life. Lastly, I would like to thank Teng for her love and solid support during this long dissertation journey. I will never forget the moment I met her by the River Cam the first day I stepped into my college. Meeting and marrying her in Cambridge is the greatest gift from heaven. I dedicate this thesis to my parents and my lovely wife. Table of Contents Declaration............................................................................................................................................. 2 Abstract .................................................................................................................................................. 3 Publication ............................................................................................................................................. 4 Presentation ........................................................................................................................................... 4 Acknowledgments ................................................................................................................................. 5 Table of Contents .................................................................................................................................. 6 Abbreviations ...................................................................................................................................... 10 Chapter 1 Introduction ....................................................................................................................... 14 1.1 Obesity and Lipid Metabolism .................................................................................................... 14 1.1.1 Obesity, Energy Homeostasis, and Metabolic Syndrome .................................................... 14 1.1.2 Sources of Fats and Lipid Synthesis .................................................................................... 15 1.1.3 Lipolysis and Oxidation of Fats ........................................................................................... 18 1.1.4 Transport of Fats and Cholesterols ...................................................................................... 20 1.1.5 Diseases and Ectopic Fat Storage ........................................................................................ 21 1.2 Adipose Tissue ............................................................................................................................ 23 1.2.1 Regulation of Adipogenesis ................................................................................................. 24 1.2.2 Lipid Metabolism in Adipocytes .......................................................................................... 25 1.2.3 Adipose Tissue Hormones and Cytokines ........................................................................... 27 1.2.4 Adipose Tissue and Inflammation ....................................................................................... 27 1.3 Regulation of Lipid Acyl Composition ....................................................................................... 29 1.3.1 Elongases and Desaturases ................................................................................................... 31 1.3.2 Sterol Regulatory Element-binding Proteins (SREBPs) ...................................................... 36 1.4 Epigenetics and One-carbon metabolism .................................................................................... 38 1.5 Mass Spectrometry in Metabolomics and Lipidomics ................................................................ 39 1.5.1 Generating Ions: Ionisation .................................................................................................. 40 1.5.2 Mass Analyser and Direct Infusion-Mass Spectrometry.....................................................
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