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REGULATION of GLUCOSE UPTAKE and TRANSPORTER EXPRESSION in the NORTH PACIFIC SPINY DOGFISH (SQUALUS SUCKLEYI) Courtney A. Deck

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REGULATION of GLUCOSE UPTAKE and TRANSPORTER EXPRESSION in the NORTH PACIFIC SPINY DOGFISH (SQUALUS SUCKLEYI) Courtney A. Deck REGULATION OF GLUCOSE UPTAKE AND TRANSPORTER EXPRESSION IN THE NORTH PACIFIC SPINY DOGFISH (SQUALUS SUCKLEYI) Courtney A. Deck, B.Sc. Thesis submitted to the University of Ottawa’s Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the Doctorate in Philosophy degree in Biology. Department of Biology Faculty of Science University of Ottawa © Courtney A. Deck, Ottawa, Canada, 2016 DEDICATION This thesis is dedicated to Wyatt Stasiuk, who was taken from us far too soon. He was the sweetest little angel and I love and miss him very much. Rest in peace baby boy. ii ABSTRACT Elasmobranchs (sharks, skates, and rays) are a primarily carnivorous group of vertebrates that consume very few carbohydrates and have little reliance on glucose as an oxidative fuel, the one exception being the rectal gland. This has led to a dearth of information on glucose transport and metabolism in these fish, as well as the presumption of glucose intolerance. Given their location on the evolutionary tree however, understanding these aspects of their physiology could provide valuable insights into the evolution of glucose homeostasis in vertebrates. In this thesis, the presence of glucose transporters in an elasmobranch was determined and factors regulating their expression were investigated in the North Pacific spiny dogfish (Squalus suckleyi). In particular, the presence of a putative GLUT4 transporter, which was previously thought to have been lost in these fish, was established and its mRNA levels were shown to be upregulated by feeding (intestine, liver, and muscle), glucose injections (liver and muscle), and insulin injections (muscle). These findings, along with that of increases in muscle glycogen synthase mRNA levels and muscle and liver glycogen content, indicate a potentially conserved mechanism for glucose homeostasis in vertebrates, and argue against glucose intolerance in elasmobranchs. In contrast to the other tissues examined, there was a decrease in glut4 mRNA levels within the rectal gland in response to natural feeding, a factor known to activate the gland, suggesting mRNA storage for rapid protein synthesis upon activation. A similar trend was also shown for sglt1 in the rectal gland, and the ability of GLUT and SGLT inhibitors to prevent chloride secretion solidified the importance of glucose uptake for gland function. The exogenous factor of salinity was also investigated and high levels of glut mRNA were observed within the rectal glands of low salinity-acclimated fish relative to control and high salinity fish, reiterating the idea of mRNA storage when the gland is expected to be inactive. Taken together, the results of this thesis iii demonstrate that glucose is an important fuel in the dogfish (and likely other elasmobranchs) and that the dogfish is fully capable of regulating its storage and circulation, contrary to prior beliefs. iv RÉSUMÉ Les élasmobranches (requins, rajidaes et raies) sont un groupe de vertébrés principalement carnivores qui consomment très peu d'hydrates de carbone et qui dépendent peu du glucose en tant que carburant oxydatif, avec l'exception de la glande rectale. Ainsi, il y a un manque d'information sur le transport et le métabolisme du glucose chez ces poissons, en plus d'une présomption qu'ils sont intolérants au glucose. Cependant, étant donné leur emplacement sur l'arbre phylogénétique, la compréhension de ces aspects de leur physiologie pourrait offrir des informations précieuses quant à l'évolution de l'homéostasie du glucose chez les vertébrés. Dans cette thèse, la présence de divers transporteurs de glucose a été déterminée chez les élasmobranches et les holocéphales. De plus, des facteurs biotiques et abiotiques qui régulent l'expression et l'activité de ces transporteurs ont été étudiés chez l'aiguillat commun du Pacifique Nord (Squalus suckleyi). En particulier, la présence d'un transporteur GLUT4 putatif, que l'on pensait auparavant avoir été perdu chez ces poissons, a été établie et il a été démontré que son niveau d'ARNm est régulé de façon positive par l'alimentation naturelle (intestin, foie et muscle), les injections de glucose (foie et muscle), et les injections d'insuline (muscle). Ces résultats, en plus de l'augmentation des niveaux d'ARNm de glycogène synthase dans le muscle, et l'augmentation du contenu de glycogène dans les muscles et le foie, indique un potentiel pour un méchanisme d'homéostasie du glucose conservé parmi les vertébrés. De plus, ces résultats plaident contre l'idée d'une supposée intolérance au glucose chez les élasmobranches. Contrairement aux autres tissus examinés, il y avait une diminution des niveaux d'ARNm pour le GLUT4 dans la glande rectale en réponse à l'alimentation naturelle, un facteur qui est connu pour son activation de la glande. Ce résultat suggère qu'il y a entreposage d'ARNm dans la glande afin de permettre à la synthèse rapide de protéines lorsqu'activée. Une tendance semblable à aussi été v démontrée pour le SGLT1 dans la glande rectale, et la capacité d'inhibiteurs de GLUT et de SGLT pour prévenir la sécrétion de chlorure a réaffirmé l'importance de l'absorption du glucose pour la fonction de la glande. La salinité en tant que facteur abiotique a également été étudiée, et de hauts niveaux d'ARNm pour le GLUT ont été observés dans les glandes rectales de poissons acclimatés à de faibles salinités, lorsque comparés à des poissons contrôles ou acclimatés à des salinités élevées. Ceci renforce l'idée qu'il y a entreposage d'ARNm lorsque la glande est supposée d'être inactive. Ensemble, les résultats de cette thèse démontrent que le glucose est un carburant important chez les aiguillats (et probablement chez les autres élasmobranches) et que ces poissons sont tout à fait capables de réguler l'entreposage et la circulation du glucose, contrairement aux croyances antérieures. vi ACKNOWLEDGEMENTS First and foremost, I would like to thank my supervisor Dr. Patrick Walsh for all his support and encouragement. Throughout the past five years, he has pushed me to become a well- rounded, successful scientist and provided me with all the skills necessary to pursue my passion. Pat, you have been an excellent mentor and I am so very fortunate to have been a part of your lab. I have really enjoyed working with you and I would not be where I am today without all of your support. Thank you for everything you have done and I hope that retirement treats you well! I would also like to extend a big, heartfelt thank you to Dr. Gary Anderson, whom I had the pleasure of working with during the last year of my PhD. Gary, thank you for all your help with experiments and for putting up with my incessant questions about endocrinology. You helped to make my final year a bit less stressful and I am very grateful for all your support. I am incredibly lucky to have had the opportunity to work with you and I hope that I will be able to do so again in the future. Throughout the past five years, I have worked alongside a number of amazing people who have made the journey much more enjoyable. Thank you to everyone who has been a part of the Walsh, Perry, Moon, and Gilmour labs at the University of Ottawa for your support and friendship. In particular, I would like to thank Drs. Chris LeMoine and Carol Bucking for their advice and mentorship, I could not have asked for two better lab mates. Thank you also to all my friends and colleagues from outside the university, especially those from the Goss, Anderson, and Wood labs whom I had the pleasure of working with out in Bamfield. You guys made the long days and early morning sampling times much more tolerable! vii I would also like to thank Dr. Eric Clelland from the Bamfield Marine Sciences Centre for all of his hard work in ensuring that my experiments ran smoothly, as well as my thesis committee (Dr. Tom Moon, Dr. Katie Gilmour, and Dr. Steve Cooke) for all of the advice they provided throughout my degree. And last but definitely not least, thank you to my wonderful family for all of their love and support, I would not be where I am without each and every one of you. viii TABLE OF CONTENTS DEDICATION………………………………………………………………………...ii ABSTRACT…………………………………………………………………………...iii RÉSUMÉ……………………………………………………………………................v ACKNOWLEDGEMENTS…………………………………………………………..vii TABLE OF CONTENTS……………………………………………………………..ix LIST OF FIGURES…………………………………………………………………...xiii LIST OF TABLES…………………………………………………………………….xviii LIST OF ABBREVIATIONS………………………………………………………...xix CHAPTER 1. General Introduction………………………………………................1 1.1 Elasmobranch Metabolism……………………………………………..3 1.2 Glucose Homeostasis in Fish…………………………………………...5 1.3 Glucose Transporters…………………………………………………...7 1.4 The Role of Insulin in Fish……………………………………………..11 1.5 Thesis Objectives………………………………………………….........15 CHAPTER 2. Phylogenetic analysis and tissue distribution of elasmobranch glucose transporters and their response to feeding………........................................17 2.1 Abstract……………………………………………………………………..18 2.2 Introduction………………………………………………………………....19 2.3 Materials and Methods……………………………………………...............21 2.3.1 Animals and Feeding……………………………………………...21 2.3.2 Phylogenetic Analysis…………………………………………….21 ix 2.3.3 Tissue Distribution………………………………………….........22 2.3.4 qPCR……………………………………………………………..23 2.4 Results……………………………………………………………………...26 2.4.1 Phylogenetic Analysis and Tissue Distribution……………….…26 2.4.2 Plasma and Tissue Analysis………………………………….…..27 2.5 Discussion……………………………………………………………….…35 2.6 Acknowledgments………………………………………………………....39
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