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EFFECTS of P-CASOMORPHINS on METABOLISM of DAIRY COWS

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EFFECTS of P-CASOMORPHINS on METABOLISM of DAIRY COWS EFFECTS OF p-CASOMORPHINS ON METABOLISM OF DAIRY COWS TAE-GYU KIM A thesis submitted to the University o f Glasgow in accordance with the requirements for the degree o f Doctor o f Philosophy in the Faculty o f Science Hannah Research Institute, Ayr, Scotland August, 1999. ProQuest Number: 13833981 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13833981 Published by ProQuest LLC(2019). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 GT .1.SGOW UNV-'ERSuT LIBRARY Col SUMMARY 1. The studies presented in this thesis investigated some metabolic actions of P- casomorphins in dairy cows. Three p-casomorphins (p-casomorphin-4-amide, -5 and - 7) were used. Investigations of the actions of the P-casomorphins in dairy cows require gram quantities of each peptide. This was achieved by synthesising the peptides using solid phase peptide synthesis combined with FMOC chemistry. 2. The first experiment examined possible stimulatory actions of the peptides on amino acid uptake by the mammary gland using explants of lactating rat mammary glands as a model in vitro system. There was no evidence of their actions on amino acid uptake by the mammary gland as judged by the lack of their effects on the uptakes of four amino acids (glutamate, histidine, leucine and lysine). Because of the inability to demonstrate effects of the peptides at the mammary gland level, it was decided to focus on their effects at the level of the gut. 3. As a first step, the extent of ruminal degradation of the P-casomorphins was determined in incubations in rumen liquor in vitro. All three peptides were degraded rapidly with half-lives of only 15 to 20 minutes. In a subsequent experiment, an attempt was made to chemically protect the peptides from the ruminal degradation using N-terminal acetylation. The half-lives of the N-acetyl p-casomorphins were markedly increased to 6 j , 1~ and 4 hours for P-casomorphin-4-amide, -5 and -7 respectively. However, it was recognised that, whilst the method would be a simple and effective method for the protection of the peptides, further developments of the method would be necessary to ensure their release in active form at their sites of their action in vivo. 4. In experiments on the actions of the (3-casomorphins in vivo, the peptides were infused direct into the abomasum. The first experiment compared hormonal responses to the abomasal infusion of sodium caseinate, a potential source of P-casomorphins, and an acid hydrolysate of casein, which was not a potential source of P-casomorphins. There were clear suggestions of differences in responses of some hormones, notably insulin and GIP. In the second experiment, effects of abomasal infusions of mixtures of the P- casomorphins themselves at three different dose levels on changes in concentrations of the hormones were investigated in lactating dairy cows. There was no clear effect of the P-casomorphin infusions on insulin concentrations except for some tendency towards inhibition at some time points. However, the incremental response of glucagon to the P-casomorphin infusions was linearly increased (P < 0.05) leading to statistically significant decreases in the insulin / glucagon ratio at 4 hours by all p-casomorphin infusions compared with control. 5. In the final section of the thesis, attention was focused on the possible inhibitory effects of the p-casomorphins on insulin secretion. Three experiments were carried out. Experiment 1 was designed to detect the inhibitory action of the P-casomorphins on the insulin level prestimulated by an abomasal infusion of glucose. The insulin concentration rise was significantly inhibited by the P-casomorphins (P < 0.05). The inhibitory action of P-casomorphin was shown to be compatible with the action of SS- 28 as judged from the effects of SS-28 on the insulin secretion when administered intravenously in the same experiment. However, the inhibitory action was not evident in the next experiment in which lactating animals were used, probably because of differences in the sensitivity of insulin secretion in lactating versus non-lactating animals. The final experiment confirmed the insulinopenic effect of the P- casomorphins by demonstrating their inhibitory action on the insulin concentrations prestimulated by an intravenous infusion of glucose. II 6 . Taken together, the results of the experiments described show effects of P-casomorphin infusions on circulating levels of hormones in the ruminant. The most pronounced effect was the modulation of the insulin response to abomasal or intravenous administration of glucose. Ill DECLARATION This thesis has been compiled by myself and has not been offered in any previous application for a degree. With the exceptions of 1) feed and milk analysis by Mrs. I. Stewart and Mr. J. Davidson, 2) GLP-1 RIA in Experiment 1 of Chapter 5 by Dr. P. Martin and 3) IGF-1 RIA in Experiment 1 of Chapter 5 by Mrs. M. Gardner, I declare that all the work contained in this thesis is my own, undertaken under the supervision and guidance of Drs D. G. Chamberlain, J. -J. Choung, D. B. Shennan and R. J. Wallace. Tae-Gyu Kim IV ACKNOWLEDGEMENTS Firstly, I would like to thank my supervisor, Dr. David Chamberlain, without whom this work and thesis would not have been possible. I am equally indebted to Dr. Jai-Jun Choung, Dr. David Shennan, at the Hannah Research Institute, and Dr. John Wallace, at the Rowett Research Institute for their advice and guidance throughout the course of my research. I would also like to thank the Director and the Council of the Hannah Research Institute and the Rowett Research Institute for providing the facilities to carry out the study, and the British Council and the Korean Collaboration Centre for Biotechnology and Biological Sciences for providing me with fellowship. My thanks go to Mr. James Davidson, Ms. Margarett McLelland, Mrs. Irene Stewart, Mrs. Evelyn Mitchell, Ms. Sandra McNeillie and Mrs. Margarett Gardner at the Hannah, and Mrs. Nest McKain and Mrs. Nicola Walker at the Rowett for their support in the collection and analyses of data. Thanks are also due to Mr. John Munro and his staff for the care and management of animals. I am also grateful to Derek, Elaine, Ellis, Ian, Lynn and Maria for their helping hand and friendship. I would like to take the opportunity to thank all Koreans at the Hannah who has kept me entertained in a traditional (?) way for many years despite the Scottish weather, which can, sometimes, be depressing! Finally, I would like to thank my parents and parents-in-law for their continuous support and prayers. However, my biggest thank must go to my wife, Eun-Joung and my daughter, Eugene who have always been by my side cheering me up throughout the difficult years. V TABLE OF CONTENTS S u m m a r y I D e c l a r a t io n IV A cknowledgements V T a b l e O f C o n t e n t s VI L ist O f F ig u r e s X L ist O f T a b l e s XIII L ist O f A bbreviations XV C h a p t e r O n e : R e v ie w O f L it e r a t u r e 1.1. Introduction 1 1.2. P r o t e in D ig e st io n In T h e R u m in a n t 2 1.2.1. Characteristics of the digestive tract of the ruminant 2 1.2.2. Ruminal digestion of protein 4 1.2.3. Post-ruminal digestion of protein 8 1.2.4. Absorption of the end products of protein digestion 12 Amino acid transport in the small intestine 15 Peptide transport in the small intestine 16 1.3. P r o t e in M e t a b o l is m In T h e D a ir y C o w 19 1.3.1. Uptake and utilisation of amino acids and peptides by the mammary gland 20 1.3.2. Milk production responses to post-ruminal supplements of casein 22 1.4. B io a c t iv e P e pt id es F r o m M ilk P r o t e in 25 1.4.1. P-Casomorphins : Discovery and chemical and biological identity 25 1.4.2. Pharmacophysiological actions of p-casomorphins 30 1.5. H o r m o n a l R e g u l a t io n O f N u t r ie n t U se 34 1.5.1. Nutrient partitioning by metabolic hormones in lactation 34 1.5.1.1. Insulin 34 1.5.1.2. Glucagon 39 1.5.1.3. Growth hormone, IGF-I and the somatostatin axis 41 1.5.2. Gut hormones and the entero-insular axis 46 1.6. A im s A n d O b je c t iv e s 51 C h a p t e r T w o : M a t e r ia l s a n d m e t h o d s 2.1.
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