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Characterization of Leptin Signaling in the Developing CHARACTERIZATION OF LEPTIN SIGNALING IN THE DEVELOPING ZEBRAFISH (Danio rerio) USING MOLECULAR, PHYSIOLOGICAL, AND BIOINFORMATIC APPROACHES A Dissertation Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy Mark Dalman December, 2014 CHARACTERIZATION OF LEPTIN SIGNALING IN THE DEVELOPING ZEBRAFISH (Danio rerio) USING MOLECULAR, PHYSIOLOGICAL, AND BIOINFORMATIC APPROACHES Mark Dalman Dissertation Approved: Accepted: ___________________________ __________________________________ Advisor Committee Member Dr. Richard L. Londraville Dr. Qin Liu ___________________________ __________________________________ Committee Member Committee Member Dr. Zhong-Hui Duan Dr. Brian Bagatto ___________________________ __________________________________ Committee Member Dean of the College Dr. Ahmed Mustafa Dr. Chand Midha ___________________________ __________________________________ Department Chair Interim Dean of the Graduate School Dr. Monte Turner Dr. Rex Ramsier __________________________________ Date ii ABSTRACT In this dissertation, I tested the hypothesis that leptin A in zebrafish (D. rerio) plays a similar role to mammalian leptin in regulating metabolic rate and immune function, whereas leptins’s effects on the zebrafish transcriptome may be distinct. Leptin is now identified in all major vertebrate lineages, but its role in controlling food intake, development, metabolic rate, and fat storage is best studied in mammals. In that group, leptin has pleiotropic effects including those on angiogenesis, bone formation, reproductive status, immune function, and energy expenditure. A homozygous mutation (ob-/ ob-) for leptin is the most common model for leptin study in mammals. The use of leptin-null mutants in non-mammal models is not common. We recently developed a leptin knockdown model in zebrafish and applied a comparative approach to studying some well-characterized mammalian leptin functions in this new system. I tested the impact of leptin expression on metabolism in the developing zebrafish embryo. Leptin knockdown reduced oxygen consumption most prominently during early development (24-48 hours post fertilization, hpf) whereas carbonic acid production was most significantly attenuated later in development (48-72 hpf). Cardiac output was significantly reduced in embryos with reduced leptin expression (leptin morphants); all of these effects could be rescued by co-injection of recombinant fish leptin. The second part of my research focused on the innate immune response. When presented with a bacterial challenge, leptin morphants had reduced macrophage respiratory burst activity and bacterial load clearance was unaffected 12 hours post iii infection (hpi). By 36 hpi, leptin morphants had significantly increased bacterial burden and reduced survival compared to control embryos. I then focused on the transcriptomic effects of reduced leptin A expression in the developing zebrafish embryo. Microarray analysis identified sensory and development pathways as the most significantly enriched in embryos with leptin expression (at a variance with mammalian adult microarray studies). Citrate synthase, 3-hydroxy acyl- CoA dehydrogenase, and carnitine palimitoyltransferase enzyme assays confirmed the general pattern of reduced aerobic respiration transcripts in leptin morphants. Furthermore, confirmation of microarray by enzyme assays found leptin morphants to have reduced enzymes in fatty acid oxidation and general aerobic respiration. The microarray study was complemented by an analysis of techniques used to filter microarray data. I found that choice of the selection criteria used during analysis can significantly impact data interpretation. I proposed that simultaneous use of two types of cutoffs (significance and fold change) was a ‘best practice’ in microarray analysis. These studies are among the first to quantify effects of leptin knockdown in the developing zebrafish embryo. Leptin function in nonmammals is conserved with mammalian leptin function in the dimensions of metabolic rate and immune function; its effects on the transcriptome (sensory and developmental pathways) differ from similar studies in mammals. This may reflect an adult bias in mammalian leptin studies. iv DEDICATION For my parents: Richard and Melody Dalman. You stood unwavering by my side through this and I couldn’t have asked for more. To my beautiful, smart daughters: Isabella and Mackensie. I know you’ve only just started first grade, but I want you to know that I am humbled by the daughters you have been and excited to see the daughters you will become. I am so very proud of you two and I am positive you will change the world. v ACKNOWLEDGEMENTS I would like to whole-heartedly thank my members of my PhD committee, Dr. Richard Londraville, Dr. Qin Liu, Dr. Zhong-Hui Duan, Dr. Ahmed Mustafa, and Dr. Brian Bagatto. Thank you for your words of encouragement, your expertise, and your time. I am truly indebted to you for providing the research opportunities and scholarly experiences I cherish to this day. I would also like to thank many undergraduate and graduate students who have helped me throughout my PhD. Graduate students: Donald Copeland, Hope Ball, Justin Brantner, and Anthony Deeter. Undergraduate students: Mason King, Michael Graves, Jessica Bucher, and Richard Ngo. Thank you for your support and advice. To my best friends John and Dee Warnock, I couldn’t have asked for better friends. To Dr. Amy Hollingsworth- thank you for listening and keeping me sane. vi TABLE OF CONTENTS Page LIST OF TABLES .............................................................................................................. x LIST OF FIGURES ........................................................................................................... xi CHAPTER I.GENERAL INTRODUCTION ........................................................................................ 1 Mammalian Leptin Signaling ................................................................................. 2 Leptin’s Mode of Activation and Signaling Pathways ........................................... 5 The Adipostat Model of Leptin Signaling .............................................................. 7 Development of Leptin Resistance ......................................................................... 9 Leptin Signaling and Secondary Effects ............................................................... 10 Development ......................................................................................................... 11 Reproduction ......................................................................................................... 12 Immune Function .................................................................................................. 12 Leptin in Fishes ..................................................................................................... 14 Identification of Fish Leptin and Questionable Role as an Adipostat .................. 15 Fish Leptin’s Role in Metabolism, Immune Function, and the Transcriptome .... 18 Overview of projects ............................................................................................. 21 vii II. LEPTIN EXPRESSION AFFECTS METABOLIC RATE IN ZEBRAFISH EMBRYOS (D. RERIO) ................................................................................................... 23 Introduction ........................................................................................................... 23 Materials and Methods .......................................................................................... 26 Results ................................................................................................................... 29 Discussion ............................................................................................................. 34 Acknowledgements ............................................................................................... 38 III.LEPTIN-A KNOCKDOWN SIGNIFCANTLY ALTERS INNATE IMMUNE RESPONSE AND IMMUNOCOMPETENCE OF DEVELOPING ZEBRAFISH EMBRYO ......................................................................................................................... 39 Introduction ........................................................................................................... 39 Methods................................................................................................................. 43 Results ................................................................................................................... 46 Discussion ............................................................................................................. 51 IV. MICROARRAY ANALYSIS OF LEPTIN-A KNOCKOUT IN EARLY ZEBRAFISH DEVELOPMENT ...................................................................................... 55 Introduction ........................................................................................................... 55 Methods................................................................................................................. 58 Results ................................................................................................................... 63 Discussion ............................................................................................................. 92 viii V. FOLD CHANGE AND P-VALUE CUTOFFS SIGNIFICANTLY ALTER MICROARRAY INTERPRETATIONS .......................................................................
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