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Estradiol Radioimmunoassay INFORMATiON TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. 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Bell & Howell Information and Learning 300 North Zeeb Road, Ann Arbor, MI 48106-1346 USA 800-521-0600 THE ROLES OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) IN TEE MOUSE BRAIN Julie Kim A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Physiology University of Toronto O Copyright by Julie Kim (1 998) National Library Bibliotheque nationale 1+1 , du Canada Acquisitions and Acquisitions et Bibliographic Services services bibliographiques 395 Wellington Street 395, rue Wellington Ottawa ON KIA ON4 Ottawa ON KIA ON4 Canada Canada your lire Vorre refence Our Ne Notre refdrence The author has granted a non- L'auteur a accorde une licence non exclusive licence allowing the exclusive pernettant a la National Library of Canada to Bibliotheque nationale du Canada de reproduce, loan, distribute or sell reproduire, preter, distribuer ou copies of this thesis in microfom, vendre des copies de cette these sous paper or electronic formats. la forme de microfiche/fh, de reproduction sur papier ou sur format electronique. The author retains ownership of the L'auteur conserve la propriete du copyright in this thesis. Neither the droit d'auteur qui protege cette these. thesis nor substantial extracts fiom it Ni la these ni des extraits substantiek may be printed or otherwise de celle-ci ne doivent 6eimprimes reproduced without the author's ou autrernent reproduits sans son permission. autorisation. THE ROLES OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) IN THE MOUSE BRAIN Master of Science, 1998 Julie Kim Department of Physiology, University of Toronto ABSTRACT Glucagon-like peptide- 1 (GLP- 1) is a gut-brain hormone synthesized by peptidergic cleavage of proglucagon in the pancreatic A cells and the L cells of the ileal mucosa. GLP-1 is involved in the regulation of pancreatic and gastric functions, stimulating insulin secretion and inhibiting gastric secretion, respectively. Although GLP-1 has been postulated to regulate food intake, mice with targeted disruption of the GLP- 1 receptor (GLP-1 R -/- mice) exhibit normal body weights, suggesting that GLP-1 is not an exclusive determinant of the central mechanisms controlling appetite. The objective of this thesis was to further explore potential central sites of GLP-1 action by mapping the distribution of its receptors in the mouse brain as well as by studying the endocrine consequences of the loss of GLP-1 receptor mediated responses, in the GLP-IR -1- mouse. Quantitative autoradiography demonstrates extensive distribution of GLP-I receptors in the diencephalon and in the limbic system, suggesting that rather than specifically regulating appetite, GLP-I may in fact play a role in a number of neuronal systems that influence neuroendocrine hction and behavior. In studying GLP-1R -1- mice from birth to adulthood, we found that while they appear phenotypically similar from the control wildtype mice (GLP- 1R +I+), their reproductive development is subtly impaired. In addition, loss of GLP-I signaling results in slight deficits in their stress responses. Responses to mild stress are subnormal, although responses to severe stress remain intact in GLP-1R -/- animals. These data suggest that GLP-1 may play a subtle modulatory role in the CNS in regulating neuroendocrine mechanisms involved in regulating reproductive function and the control of adrenal function, in addition to its postulated involvement in the regulation of food intake. Several people have been cited for having made contributions to this thesis: Drs. Daniel J. Drucker and Louise A. Scrocchi were responsible for generating mice with targeted disruption of the GLP- I receptor and also for supplying both wildtype and GLP-1R -/- mice; Dr. Patricia L. Brubaker synthesized radiolabeled [125~]-~~~-1-(7-36)and ['25~]-exendin-4; Dr. Richard Hochberg provided radiolabeled 1 1P-rnethoxy 16a[125~]-iodo estradiol WE2); Dr. Sylvia Asa performed histological examinations. In addition, there are a number of people I wish to acknowlegde for making this thesis possible. First, I owe a debt of gratitude to my supervisor Dr. Neil J. MacLusky for his instructed guidance and constant encouragement. I would also like to thank Dr. Theodore J. Brown for his generosity of time and helpfid assistance in the lab. To Alexandra Kollara and Andreas Evangelou, I owe special thanks for their friendship and unlimited supply of energy- boosting Hersheys hugs & kisses. To Deboleena Roy and Shirya Rashid, I thank them for all their encouragement. I also thank Heather Edwards and Arawn Therrien for their practical wisdom and amusing insights that men are from mars. A special thanks to my cousidroommate Moon-Sook Kyun for Girlfriends' Nites and for always being there for me, especially when soot almost gave us the BIG boot! Special thanks to Davey Chung for his unparalleled sense of humor, sushi and Garth Brooks that only he can sing to. To my faithfid friend, Cei-Whan Kim, I thank him for 'peas & carrots', for all his prayers, and especially for his classical guitar playing - Cei, you've got it nailed! To Byron Carter, Shelley MacDonald and the rest of my family at the Toronto Baptist Fellowship, I thank them for all their prayers and support. Finally, to my parents, Dr. Kwang Oh Kim and Myung Ja Paik, I owe them a debt of gratitude for being unfkilingly supportive and immensely loving. And to Jurny, Juan and Justin, my awesome .lK3 siblings, I thank God for blessing me with them. Last but certainly not least, I give eternal thankfulness to God for being my FaiWl Rock and for guiding me to The Meeting Place (Toronto)! (iv.) Emulsion A utoradiography................................................................................. 22 2.5 DISCUSSION ............................................................................................................ 42 GLP-1R -/- MOUSE MODEL ....................................... 45 PRELIMINARY OBSERVATIONS IN GLP-I R -/- MICE................... .. .................... 45 OBJECTIVE...................................................................................................................... 46 MATERIALS AND METHODS ..................................................................................... -47 (i.) Animal Breeding .................................................................................................... 47 (ii.) Vaginal Opening Inspection .............................................................................. 47 ... (rrr.) Tissue Dissection ............................................................................................... -47 (iv.) GLP-I Receptor Autoradiography ...................................................................... 48 (v.) Gonadal Histology ................................................................................................ 48 (vi.) Radioirnrnunoassay ............................................................................................. -48 .. (vzr.) Statistical Analysis ............................................................................................ -49 RESULTS ......................................................................................................................... 50 (i.) Deficits in GLP-I R -1- Reproductive Functions.................................................... 50 (ii.) Examining GLP-I R -1- Testes and Ovaries.................................................. 51 (iii.) Esrradiol. Testosterone. and Corticosterone Radioimmunoassuy...................... 51 DISCUSSION ................................................................................................................... 66 CHAPTER LV . lRlPLICATIONS OF GLP-1 IN THE CONTROL OF APPETITE............................. ,. ....... 70 ROLE OF CCK-8 IN APPETITE CONTROL ............................................................... 70 OBJECTIVE..................................................................................................................... 72 MATERIALS AND METHODS...................................................................................... 73 (i.) Chemicals............................................................................................................
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