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Davey KJ Phd 2013.Pdf UCC Library and UCC researchers have made this item openly available. Please let us know how this has helped you. Thanks! Title The gut microbiota as a contributing factor to antipsychotic-induced weight gain and metabolic dysfunction Author(s) Davey, Kieran Publication date 2013 Original citation Davey, K. 2013. The gut microbiota as a contributing factor to antipsychotic-induced weight gain and metabolic dysfunction. PhD Thesis, University College Cork. Type of publication Doctoral thesis Rights © 2013. Kieran Davey http://creativecommons.org/licenses/by-nc-nd/3.0/ Embargo information Restricted to everyone for one year Item downloaded http://hdl.handle.net/10468/1243 from Downloaded on 2021-10-09T20:00:22Z Ollscoil na hEireann National Unversity Ireland Colaiste na hOllscoile, Corcaigh University College Cork School of Pharmacy The Gut Microbiota as a Contributing Factor to Antipsychotic-Induced Weight Gain and Metabolic Dysfunction Thesis presented by Kieran J. Davey under the supervision of Prof. John F. Cryan Prof. Timothy G. Dinan Dr Siobhain M. O’Mahony for the degree of Doctor of Philosophy Head of School: CatrionaO’Driscoll Contents Declaration ........................................................................................................................................... vii Acknowledgements .......................................................................................................................... viii Publications and presentations ...................................................................................................... ix List of abbreviations……………..……………………………………………………………………………xi Abstract……………………………………………………………………………………………………………xv Chapter 1 General Introduction ............................................................................................. 1 1.1 Schizophrenia .................................................................................................................................. 2 1.1.1 Neurochemistry of schizophrenia .................................................................................. 4 1.2 Treatment of schizophrenia ...................................................................................................... 6 1.2.1 Typical antipsychotics ......................................................................................................... 6 1.2.2 Side effects of typical antipsychotics ............................................................................. 7 1.2.3 Atypical antipsychotics ....................................................................................................... 8 1.2.4 Typicality versus atypicality .......................................................................................... 12 1.3 Body weight regulation ............................................................................................................ 14 1.3.1 Energy intake ....................................................................................................................... 16 1.3.1.1 Hypothalamic Regulation of Food Intake .............................................................. 17 1.3.2 Peripheral Signals in the Regulation of Energy Balance ..................................... 25 1.3.3 Energy Storage .................................................................................................................... 28 1.3.3 Energy Expenditure ........................................................................................................... 30 1.4 Obesity ............................................................................................................................................ 31 1.4.1 Obesity and energy intake .............................................................................................. 32 1.4.2 Obesity and energy storage ............................................................................................ 33 1.4.3 Obesity and energy expenditure .................................................................................. 33 1.5 Metabolic syndrome .................................................................................................................. 34 1.5.1 Visceral Adiposity .............................................................................................................. 35 1.5.2 Inflammation ........................................................................................................................ 38 1.5.3 Insulin resistance ............................................................................................................... 39 1.5.4 Dyslipidemia ........................................................................................................................ 40 ii 1.6 Side Effects of Atypical Antipsychotics ............................................................................... 41 1.6.1 Antipsychotic-induced weight gain ............................................................................. 42 1.6.2 Antipsychotic-induced metabolic dysfunction ....................................................... 44 1.6.2.1 Antipsychotic-induced visceral adiposity ............................................................. 44 1.6.2.2 Antipsychotic-induced insulin resistance ............................................................. 45 1.6.2.3 Antipsychotic-induced inflammation ..................................................................... 46 1.6.2.4 Antipsychotic-induced dyslipidemia ....................................................................... 47 1.7 Pharmacology of atypical Antipsychotics: metabolic side Effects ........................... 56 1.7.1 Dopamine receptors .......................................................................................................... 56 1.7.2 Serotonin Receptors .......................................................................................................... 58 1.7.3 Histamine Receptors ......................................................................................................... 59 1.7.4 Muscarinic Receptors ....................................................................................................... 60 1.7.5 Adrenergic Receptors ....................................................................................................... 61 1.8 Predisposition to antipsychotic side effects ..................................................................... 62 1.9. Schizophrenia and obesity ..................................................................................................... 63 1.10 Animal models of metabolic side effects of antipsychotics ..................................... 64 1.11 Gut microbiota ........................................................................................................................... 66 1.11.1 Establishment of the gut microbiota ........................................................................ 67 1.11.2 Microbiota taxonomy and composition .................................................................. 67 1.11.3 Gut microbiota and energy regulation .................................................................... 70 1.11.3.1 Microbiota and adiposity .......................................................................................... 71 1.11.4 Microbiota and Metabolic Disease ............................................................................ 74 1.11.4.1 Microbiota and Inflammation .................................................................................. 75 1.11.4.2 Microbiota and insulin resistance ......................................................................... 76 1.11.5 Microbiota composition and obesity ........................................................................ 77 1.11.6 Brain-gut-microbiota axis ............................................................................................ 81 1.11.6.1 Microbiota and the CNS ............................................................................................. 82 1.11.7 Measuring the gut microbiota ..................................................................................... 84 1.12 Linking the gut microbiota and antipsychotic side effects ...................................... 86 1.13 Aims of thesis ............................................................................................................................. 88 1.13.1 Can a mouse-based model of antipsychotic weight gain be established? .. 88 iii 1.13.2 Do rats incur weight gain and metabolic dysfunction in response to olanzapine? ...................................................................................................................................... 88 1.13.3 Does the microbiota potentially represent a therapeutic target for antipsychotic-induced metabolic dysfunction? ................................................................. 89 Chapter 2 Olanzapine increases visceral fat independent of body weight in a sex-specific manner in the mouse ...................................................................................... 90 Abstract .................................................................................................................................................. 91 2.1 Introduction .................................................................................................................................. 92 2.2 Methods .........................................................................................................................................
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