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Zhang Metabolic Energy Balances in Ketotic Rat METABOLIC ENERGY BALANCES IN KETOTIC RAT BRAIN by YIFAN ZHANG Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Joseph C LaManna, PhD Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY August, 2013 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Yifan Zhang candidate for the Doctor of Philosophy degree*. Xin Yu , Sc. D Joseph C. LaManna, Ph.D Zhenghong Lee, Ph.D Michelle. A. Puchowicz, Ph.D Gerald . M. Saidel, Ph.D Kingman. P. Strohl, M.D (date) May 14th, 2013 * We also certify that written approval has been obtained for any proprietary material contained therein. ii Table of Contents METABOLIC ENERGY BALANCES IN KETOTIC RAT BRAIN ........................... I DEDICATION............................................................................................................... VII ACKNOWLEDGMENT ............................................................................................. VIII ABSTRACT ..................................................................................................................... IX LIST OF FIGURES ........................................................................................................ XI LIST OF TABLES ....................................................................................................... XIII ACRONYMS ................................................................................................................ XIV CHAPTER 1 OVERVIEW OF THE DISSERTATION ............................................... 1 CHAPTER 2 BACKGROUND ........................................................................................ 5 2.1 BIOCHEMISTRY OF KETONE BODIES ............................................................................. 5 2.1.1 Ketone and ketone bodies ...........................................................................................5 2.1.2 Pathways and regulations of ketone bodies’ metabolism ...........................................6 2.2 KETOSIS AND METHODS OF INDUCTION ....................................................................... 7 2.3 NEUROPROTECTION FROM KETOSIS ............................................................................ 9 2.3.1 Ketosis as a pre-conditioning for protection ..............................................................9 2.3.2 Ketosis as a therapy ....................................................................................................9 2.4 METABOLISM OF GLUCOSE AND KETONE BODIES. ..................................................... 12 2.5 OVERVIEW OF METHODS TO ESTIMATE THE CMR ................................................... 14 2.5.1 KETY-SCHMIDT METHOD (MEASUREMENT OF UPTAKE) ...................................... 15 2.5.2 Compartmental Modeling method (Measurement of reaction) ................................15 2.5.3 Inherent difficulties to determine the CMR ...............................................................17 2.6 UNPUBLISHED PILOT STUDIES ON CMRGLC AND OXIDATIVE METABOLISM ........... 19 2.6.1 Common mistakes and precautions in determining the CMRglc by FDG-PET .........19 2.6.2 Animal Anesthesia System Development ..................................................................20 iii 2.6.3 Unreported CMRglc data ...........................................................................................22 2.6.4 Unreported CMRglc meta-analysis data ....................................................................24 2.7 FIGURES AND TABLES ................................................................................................. 25 CHAPTER 3 KETOSIS PROPORTIONATELY SPARES GLUCOSE UTILIZATION IN BRAIN ............................................................................................ 33 3.1 ABSTRACT ................................................................................................................... 34 3.2 INTRODUCTION ........................................................................................................... 35 3.3 MATERIALS AND METHODS ........................................................................................ 38 3.3.1 Animal Model and Diets ...........................................................................................38 3.3.2 Anesthesia and Surgery .............................................................................................39 3.3.3 Physiological Parameters .........................................................................................40 3.3.4 Image Acquisition and Blood Sampling ....................................................................40 3.3.5 Image Processing: Region and Volumes of Interest .................................................42 3.3.6 Parameter Estimation and Calculation of CMRglc ...................................................43 3.4 RESULTS ...................................................................................................................... 45 3.4.1 Physiological parameters .........................................................................................45 3.4.2 Cerebral Glucose Metabolic Rates ...........................................................................45 3.4.3 Meta-analysis of CMRglc in Ketotic Subjects ............................................................46 3.5 DISCUSSION ................................................................................................................. 48 3.6 ACKNOWLEDGEMENTS ............................................................................................... 52 3.7 FIGURES AND TABLES ................................................................................................. 53 CHAPTER 4 CONTRIBUTIONS OF BRAIN GLUCOSE AND KETONE BODIES TO OXIDATIVE METABOLISM ................................................................................ 63 4.1 ABSTRACT ................................................................................................................... 64 4.2 INTRODUCTION ........................................................................................................... 65 iv 4.3 METHODS .................................................................................................................... 67 4.3.1 Animal Preparation and Diets ...............................................................................67 4.3.2 Experimental Design, Tracer Preparation, and Infusions .....................................68 4.3.3 Estimation of the Contribution of Acetoacetate and Glucose to Oxidative Metabolism .................................................................................................................69 4.4 RESULTS AND DISCUSSIONS........................................................................................ 70 4.5 Acknowledgments .........................................................................................................72 4.6 Figures and tables........................................................................................................73 CHAPTER 5 KETONE BODIES SPARES GLUCOSE OXIDATIVE METABOLISM IN DIET-INDUCED KETOSIS IN RAT BRAIN ........................... 76 5.1 ABSTRACT ................................................................................................................... 76 5.2 INTRODUCTION ........................................................................................................... 78 5.3 METHODS .................................................................................................................... 82 5.3.1 Animal model and diets .............................................................................................82 5.3.2 Tracer Infusion and tissue collection ........................................................................82 5.3.3 Analytical method and theory of flux analysis ..........................................................85 5.4 RESULTS ...................................................................................................................... 87 5.4.1 Physiological parameters .........................................................................................87 5.4.2 Plasma and BHB tracer enrichments .......................................................................88 5.4.3 First turn of CAC metabolites fluxes ........................................................................89 5.4.4 Pyruvate recycling and 2nd turns of CAC .................................................................90 5.4.5 Metabolite concentrations ........................................................................................92 5.5 DISCUSSION ................................................................................................................. 94 5.5.1 Changes of oxidative metabolism in ketosis .............................................................94 v 5.5.2 Shunts to neurotransmitters ......................................................................................96 5.5.3 Alterations of pyruvate recycling ..............................................................................97 5.6 ACKNOWLEDGMENT ................................................................................................. 101 5.7 FIGURES AND TABLES ............................................................................................... 102 CHAPTER 6 CONCLUSIONS & FUTURE WORKS.............................................. 114 6.1 INTRODUCTION
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