DOCSLIB.ORG

Investigation of Gut Hormone Physiology in the Regulation of Appetite

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Investigation of Gut Hormone Physiology in the Regulation of Appetite Investigation of gut hormone physiology in the regulation of appetite A thesis submitted for the degree of the Doctor of Philosophy in Imperial College London Sagen Elizabeth Kanissaril Zac-Varghese BSc (hons), MBChB, MRCP 2011 Department of Medicine, Imperial College London 1 Abstract Peptide tyrosine tyrosine (PYY) and glucagon like peptide-1 (GLP-1) are endogenous, anorectic gut hormones released from entero-endocrine L cells. The aims of this thesis were to: investigate the breakdown of PYY using peptide analogues in vitro and in vivo, determine the stimuli for release of PYY and GLP-1 from L cells in vitro and finally to attempt to stimulate the endogenous secretion of PYY and GLP-1 and so suppress appetite in man. The breakdown of PYY was studied using specially designed PYY analogues with changes to known enzyme cleavage sites. Degradation of the analogues was studied by incubation with proteolytic enzymes. Receptor binding assays were carried out to confirm that changes to the PYY structure had not altered binding to the endogenous PYY receptors. In vivo studies in rodents previously confirmed an extended pharmacological profile of these analogues. In order to study the various stimulants for PYY and GLP-1 release, a primary L cell model was developed. This was used to study the effect of various nutrients: glucose, amino acids and short chain fatty acids (SCFA) on PYY and GLP-1 release. In mouse and human primary L cell cultures the SCFA propionate increased PYY release significantly compared to basal levels, indicating that propionate is a potent stimulus of PYY release. To further investigate the results of the in vitro work, a randomised, double blind, crossover study was carried out in human volunteers to evaluate the effect of propionate on appetite. Administration of propionate ester over six days reduced energy intake at a buffet meal by 18.8% compared to control (P < 0.05, n = 20). However, there was no significant change in plasma GLP-1 or PYY levels between the groups, possibly suggesting an alternative explanation for the reduction in appetite seen. This may provide an interesting avenue for future studies. These studies of the physiological mechanisms underlying release and degradation of PYY and GLP-1 may contribute towards the development of an anti-obesity therapy based around L cell stimulation. 2 Declaration of contributors All of the work in this thesis was carried out by the author unless stated otherwise. All collaborations are listed below. Chapter 2: Development of the PYY analogue was by Professor Stephen Bloom. Testing of the analogues in animal studies was carried out by the PYY analogue team, Imperial College (Dr. Tricia Tan, Dr. Ben Field, Dr. James Minnion, Ms. Joyceline Shillito, Dr. Jordan Baxter, Dr. Melisande Addison, Dr. Mohammed Hankir, Dr. Samar Ghourab, Ms. Klara Hostomska, Ms. Jennifer Parker, Mr. James Plumer, Dr. Katherine Simpson and Dr. Victoria Salem). The clinical studies were carried out in collaboration with Dr. Victoria Salem, Dr. Tricia Tan and Dr. Ben Field. Dr. James Gardiner and Dr. Emily Thompson assisted in setting up the hY1 and hY5 receptor over-expressing cell lines. Ms. Joyceline Shillito assisted in the receptor binding assays and enzyme degradation studies. Chapter 3: Dr. Fiona Gribble, Cambridge, kindly taught me the method of primary cell culture. Dr. Jelena Anastasvoska, Dr. Benjamin Jones and Ms. Arianna Psichas assisted with these studies. Human colon biopsies were obtained by Dr. Julian Walters, Dr. Jonathan Nolan and Dr. Ian Johnston. Dr. Roger White and Dr. Jimmy Bell assisted by providing primary cell culture facilities. Chapter 4: The human study was performed in collaboration with Ms. Norlida Matt Daud. Dr. Douglas Morrison, Glasgow, provided all of the test reagents used in the study. All human studies were carried out at the Sir McMichael Centre, the Clinical Investigations Unit, Hammersmith Hospital. Dr. Michael Patterson provided assistance and advice for all of the in house radioimmunoassays carried out. Professor Mohammad Ghatei established and maintained all of the radioimmunoassays. 3 Acknowledgements I would like to thank Professor Stephen Bloom for his constant support and encouragement. I am extremely grateful to Professor Gary Frost for his enthusiasm and guidance and to Dr. Niamh Martin who has been a constant, stable and reassuring presence. I would also like to thank Dr. Tricia Tan for her integrity, support and friendship. Special thanks to Professor Mohammad Ghatei, Dr. Michael Patterson, Dr. James Minnion, Ms. Joyceline Shillito, Dr. Waljit Dhillo, Dr. Jelena Anastasvoska, Ms. Arianna Psichas and Mr. Nima Khandan-nia. I am extremely grateful to Dr. Fiona Gribble for generously teaching me the technique of primary L cell culture, a technique that had taken her four years to establish. I would like to thank the Wellcome Trust for funding my research. I am grateful to the subjects who kindly volunteered for the studies, without whose participation much of this work would have been impossible. 4 for my father and mother 5 Abbreviations AcN Acetonitrile ACTH Adrenocorticotrophic hormone AgRP Agouti related protein AMP Adenosine monophosphate AP Area postrema ARC Arcuate nucleus BMI Body mass index BSA Bovine serum albumin cAMP Cyclic adenosine monophosphate CART Cocaine- and amphetamine-regulated transcript CCK Cholecystokinin CNS Central nervous system CO2 Carbon dioxide CRH Corticotrophin-releasing hormone CSF Cerebrospinal fluid DEBQ Dutch Eating Behaviour Questionnaire DMEM Dulbecco’s Modified Eagle’s Medium DMH Dorsomedial hypothalamus DNA Deoxyribonucleic acid DPP IV Dipeptidyl peptidase IV ECG Electrocardiogram EDTA Ethylene diamine tetra-acetic acid ELISA Enzyme linked immunosorbent assay Ex-4 Exendin 4 Fmoc Fluorenyl Methoxy-Carbonyl KO Knockout GCG Glucagon 6 GDW Glass distilled water GI Gastrointestinal GIP Glucose-dependent insulinotropic peptide GLP-1 Glucagon-like peptide-1 GLP-1R Glucagon-like peptide-1 receptor GLP-2 Glucagon-like peptide-2 GRPP Glicentin-related pancreatic polypeptide GTE Glucose tris EDTA HEPES N-(2-hydroxyethyl)piperazine-N’-(2-ethanesulfonic acid); 4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid HPLC High performance liquid chromatography HPT Hypothalamo-pituitary-thyroid ICV Intracerebroventricular IP Intraperitoneal KBB Kidney brush borders LB Lysogeny broth LHA Lateral hypothalamic area MALDI-ToF Matrix-assisted laser desoption/ionization-time of flight MCH Melanin-concentrating hormone MCR Melanocortin receptor MCR2 Melanocortin-2 receptor MCR3 Melanocortin-3 receptor MCR4 Melanocortin-4 receptor MPGH Major proglucagon fragment MSH Melanocyte-stimulating hormone NDC Non digestible carbohydrate NEP Neprilysin NHS National health service 7 NPY Neuropeptide Y NTS Nucleus of the solitary tract OXM Oxyntomodulin PBS Phosphate buffered saline PEG Polyethylene glycol PEI Polyethylenimine PMSF Phenylmethylsulphonylfluoride POMC Proopiomelanocortin PP Pancreatic polypeptide PVN Paraventricular nucleus PYY Peptide tyrosine tyrosine RBA Receptor binding assay RIA Radioimmunoassay RNA Ribonucleic acid SC Subcutaneous SCFA Short chain fatty acid SDS Sodium dodecyl sulphate SP Spacer peptide SPPS Solid phase peptide synthesis TAE Tris, acetic acid, EDTA TFA Trifluoroacetic acid TRH Thyrotrophin releasing hormone TSH Thyroid stimulating hormone VAS Visual analogue scales VMH Ventromedial hypothalamus 8 Table of Contents Abstract 2 Declaration of contributors 3 Acknowledgements 4 Dedication 5 Abbreviations 6 Table of contents 9 List of figures 17 List of tables 21 1. General introduction 22 1.1 Obesity 22 1.2 Prevalence and economic cost of obesity 23 1.3 Aetiology of obesity 24 1.4 Consequences of obesity 25 1.5 Treatment of obesity 26 1.5.1 Diets 26 1.5.2 Medical treatment 28 1.5.3 Bariatric surgery 30 1.6 The hypothalamus and appetite circuits 33 1.6.1 The Arcuate nucleus (ARC) 34 1.6.2 The Paraventricular Nucleus (PVN) 35 1.6.3 The Dorsomedial Nucleus (DMN) 35 1.6.4 The Ventromedial Nucleus (VMN) 36 1.6.5 The Lateral Hypothalamic Area (LHA) 36 1.7 The brainstem, vagal nerve and appetite circuit 37 1.8 Neuropeptides and neurotransmitters involved in appetite regulation 40 1.8.1 Neuropeptide Y (NPY) 40 9 1.8.2 The melanocortin system 40 1.8.3 Cocaine and amphetamine regulated transcript (CART) 43 1.9 Peripheral adiposity hormones involved in appetite regulation 43 1.9.1 Insulin 43 1.9.2 Leptin 44 1.10 Peripheral gut hormones involved in appetite regulation 45 1.10.1 Cholecystokinin (CCK) 47 1.10.2 Glucagon-like peptide- 1 (GLP-1) 47 1.10.3 Oxyntomodulin (OXM) 51 1.10.4 Pancreatic polypeptide (PP) 51 1.10.5 Peptide YY (PYY) 52 1.10.6 Ghrelin 54 1.14 Summary 55 1.15 Hypotheses 56 1.16 Aims 57 2. Investigation into the physiological degradation of PYY3-36, using PYY analogues 2.1 Introduction 58 2.1.1 PYY degradation 59 2.1.2 Dipeptidyl peptidase IV (DPP IV) 60 2.1.3 Meprins 60 2.1.4 Neprilysin (NEP) 61 2.1.5 Design of Stable PYY analogues 61 2.1.6 NPY receptors 62 2.1.7 Y1 receptor 65 10 2.1.8 Y2 receptor 65 2.1.9 Y4 receptor 66 2.1.10 Y5 receptor 66 2.2 Aims and hypothesis 68 2.2.1 Hypothesis 68 2.2.2 Aims 68 2.3 Materials and Methods 69 2.3.1 PYY analogue - PYYα synthesis 69 2.3.2 Safety testing of PYYα 69 2.3.3 Proteolytic degradation of peptides 70 2.3.4 KBB degradation assay 70 2.3.5 Neprilysin (NEP) protease assay 71 2.3.6 Matrix- assisted laser desorption/ ionisation- Time of flight analysis (MALDI- ToF) of KBB hydrolysates 71 2.3.7 Receptor binding studies- production of hY1 and hY5 receptor
Load more

Recommended publications
  • Potential for Gut Peptide-Based Therapy in Postprandial Hypotension
    nutrients Review Potential for Gut Peptide-Based Therapy in Postprandial Hypotension Malcolm J. Borg 1, Cong Xie 1 , Christopher K. Rayner 1, Michael Horowitz 1,2, Karen L. Jones 1,2 and Tongzhi Wu 1,2,* 1 Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; [email protected] (M.J.B.); [email protected] (C.X.); [email protected] (C.K.R.); [email protected] (M.H.); [email protected] (K.L.J.) 2 Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia * Correspondence: [email protected]; Tel.: +61-8-8313-6535 Abstract: Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pool- ing. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose- dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH. Keywords: postprandial hypotension; glucagon-like peptide-1; glucose-dependent insulinotropic Citation: Borg, M.J.; Xie, C.; Rayner, polypeptide; somatostatin; diabetes mellitus; autonomic failure C.K.; Horowitz, M.; Jones, K.L.; Wu, T.
    [Show full text]
  • Effect of the Natural Sweetener Xylitol on Gut Hormone Secretion and Gastric Emptying in Humans: a Pilot Dose-Ranging Study
    nutrients Article Effect of the Natural Sweetener Xylitol on Gut Hormone Secretion and Gastric Emptying in Humans: A Pilot Dose-Ranging Study Anne Christin Meyer-Gerspach 1,2,* , Jürgen Drewe 3, Wout Verbeure 4 , Carel W. le Roux 5, Ludmilla Dellatorre-Teixeira 5, Jens F. Rehfeld 6, Jens J. Holst 7 , Bolette Hartmann 7, Jan Tack 4, Ralph Peterli 8, Christoph Beglinger 1,2 and Bettina K. Wölnerhanssen 1,2,* 1 St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland; [email protected] 2 Faculty of Medicine, University of Basel, 4001 Basel, Switzerland 3 Department of Clinical Pharmacology and Toxicology, University Hospital of Basel, 4001 Basel, Switzerland; [email protected] 4 Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, 3000 Leuven, Belgium; [email protected] (W.V.); [email protected] (J.T.) 5 Diabetes Complications Research Centre, Conway Institute University College Dublin, 3444 Dublin, Ireland; [email protected] (C.W.l.R.); [email protected] (L.D.-T.) 6 Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; [email protected] 7 Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; [email protected] (J.J.H.); [email protected] (B.H.) 8 Department of Surgery, Clarunis, St. Claraspital, 4002 Basel, Switzerland; [email protected] * Correspondence: [email protected] (A.C.M.-G.); [email protected] (B.K.W.); Tel.: +41-61-685-85-85 (A.C.M.-G.
    [Show full text]
  • Plasma Hormones Facilitated the Hypermotility of the Colon in a Chronic Stress Rat Model
    Plasma Hormones Facilitated the Hypermotility of the Colon in a Chronic Stress Rat Model Chengbai Liang, Hesheng Luo*, Ying Liu, Jiwang Cao, Hong Xia Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China Abstract Objective: To study the relationship between brain-gut peptides, gastrointestinal hormones and altered motility in a rat model of repetitive water avoidance stress (WAS), which mimics the irritable bowel syndrome (IBS). Methods: Male Wistar rats were submitted daily to 1-h of water avoidance stress (WAS) or sham WAS (SWAS) for 10 consecutive days. Plasma hormones were determined using Enzyme Immunoassay Kits. Proximal colonic smooth muscle (PCSM) contractions were studied in an organ bath system. PCSM cells were isolated by enzymatic digestion and IKv and IBKca were recorded by the patch-clamp technique. Results: The number of fecal pellets during 1 h of acute restraint stress and the plasma hormones levels of substance P (SP), thyrotropin-releasing hormone (TRH), motilin (MTL), and cholecystokinin (CCK) in WAS rats were significantly increased compared with SWAS rats, whereas vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and corticotropin releasing hormone (CRH) in WAS rats were not significantly changed and peptide YY (PYY) in WAS rats was significantly decreased. Likewise, the amplitudes of spontaneous contractions of PCSM in WAS rats were significantly increased comparing with SWAS rats. The plasma of WAS rats (100 ml) decreased the amplitude of spontaneous contractions of controls. The IKv and IBKCa of PCSMs were significantly decreased in WAS rats compared with SWAS rats and the plasma of WAS rats (100 ml) increased the amplitude of IKv and IBKCa in normal rats.
    [Show full text]
  • Inhibition of Gastrin Release by Secretin Is Mediated by Somatostatin in Cultured Rat Antral Mucosa
    Inhibition of gastrin release by secretin is mediated by somatostatin in cultured rat antral mucosa. M M Wolfe, … , G M Reel, J E McGuigan J Clin Invest. 1983;72(5):1586-1593. https://doi.org/10.1172/JCI111117. Research Article Somatostatin-containing cells have been shown to be in close anatomic proximity to gastrin-producing cells in rat antral mucosa. The present studies were directed to examine the effect of secretin on carbachol-stimulated gastrin release and to assess the potential role of somatostatin in mediating this effect. Rat antral mucosa was cultured at 37 degrees C in Krebs-Henseleit buffer, pH 7.4, gassed with 95% O2-5% CO2. After 1 h the culture medium was decanted and mucosal gastrin and somatostatin were extracted. Carbachol (2.5 X 10(-6) M) in the culture medium increased gastrin level in the medium from 14.1 +/- 2.5 to 26.9 +/- 3.0 ng/mg tissue protein (P less than 0.02), and decreased somatostatin-like immunoreactivity in the medium from 1.91 +/- 0.28 to 0.62 +/- 0.12 ng/mg (P less than 0.01) and extracted mucosal somatostatin-like immunoreactivity from 2.60 +/- 0.30 to 1.52 +/- 0.16 ng/mg (P less than 0.001). Rat antral mucosa was then cultured in the presence of secretin to determine its effect on carbachol-stimulated gastrin release. Inclusion of secretin (10(-9)-10(-7) M) inhibited significantly carbachol-stimulated gastrin release into the medium, decreasing gastrin from 26.9 +/- 3.0 to 13.6 +/- 3.2 ng/mg (10(-9) M secretin) (P less than 0.05), to 11.9 +/- 1.7 ng/mg (10(-8) secretin) (P less than 0.02), and to 10.8 +/- 4.0 ng/mg (10(-7) M secretin) (P less than […] Find the latest version: https://jci.me/111117/pdf Inhibition of Gastrin Release by Secretin Is Mediated by Somatostatin in Cultured Rat Antral Mucosa M.
    [Show full text]
  • The Gastrointestinal Cholecystokinin Receptors in Health and Diseases
    Roczniki Akademii Medycznej w Białymstoku · Vol. 50, 2005 · TheAnnales gastrointestinal Academiae cholecystokinin Medicae Bialostocensis receptors in health and diseases 21 The gastrointestinal cholecystokinin receptors in health and diseases Morisset J* Service de Gastroentérologie, Université de Sherbrooke, Canada Key words: cholecystokinin, gastrin, cholecystokinin recep- gene in different species, their localization and the results of tors, pancreas. their specific occupation under normal and pathological states. Introduction Cholecystokinin Over the years, cholecystokinin (CCK) has been accepted as A. Molecular forms the gastrointestinal hormone mainly responsible for the control Shortly after his discovery of CCK-33 in pig intestine [1], of gallbladder contraction, pancreatic enzyme secretion, growth Mutt purified the slightly larger form CCK-39 from the same of the pancreatic gland and gut motility. On the contrary, its sis- species’ intestine [5]. Later on, smaller and larger molecules ter hormone gastrin is recognized to regulate gastric acid secre- were isolated from several species’ brain and intestine. CCK-58, tion and proliferation of the acid secreting portion of the gastric 8, 5 and 4 were found in porcine brain [6] whereas the molecular mucosae as well as that of the upper intestine and colon. forms 58, 39, 33, 25, 18, 8, 7 and 5 were all identified in dog These two hormones share the same carboxy-terminal pen- intestine [7,8]. Some of these same peptides were also identified tapeptide amide sequence but differ in their sulfation sites on in bovine intestine, 39 and 33, in rat intestine, 58, 22, 8 and in the active C-terminal portion of their molecule; indeed, gastrin guinea pig intestine, 22 and 8 [9-11].
    [Show full text]
  • Gastrointestinal Hormone Actions in the Central Regulation of Energy Metabolism: Potential Sensory Roles for the Circumventricular Organs
    International Journal of Obesity (2009) 33, S16–S21 & 2009 Macmillan Publishers Limited All rights reserved 0307-0565/09 $32.00 www.nature.com/ijo REVIEW Gastrointestinal hormone actions in the central regulation of energy metabolism: potential sensory roles for the circumventricular organs TD Hoyda, PM Smith and AV Ferguson Department of Physiology, Queen’s University, Kingston, Ontario, Canada A variety of circulating signals provide essential information to the central nervous system (CNS) regarding nutritional status. The gastrointestinal system produces many such molecules that are now known to have profound effects on feeding behavior and the control of metabolism as a consequence of their ability to regulate the neural circuitry involved in metabolic homeostasis. Although many of these substances have been suggested to directly access such brain centers, their lipophobic characteristics suggest that alternative mechanisms should be considered. In this paper, we consider one such alternative, namely, that a specialized group of CNS structures collectively known as the sensory circumventricular organs (CVOs), which are not protected by the normal blood–brain barrier, may play important roles in such blood to brain communications. Specifically, we review a developing literature that shows receptors for, and functional actions of, gastrointestinal hormones such as amylin, cholecystokinin, ghrelin and peptide YY in the area postrema and subfornical organ. Collectively, these observations suggest potentially significant roles for the sensory CVOs in the regulation of energy balance. International Journal of Obesity (2009) 33, S16–S21; doi:10.1038/ijo.2009.11 Keywords: amylin; ghrelin; peptide YY; regulation of food intake; adipokines; circumventricular organs Introduction appreciation of the regulatory circuitry controlling the integration of feeding and metabolism.
    [Show full text]
  • Distribution of the Gut Hormones in the Primate Intestinal Tract
    Gut: first published as 10.1136/gut.20.8.653 on 1 August 1979. Downloaded from Gut, 1979, 20, 653-659 Distribution of the gut hormones in the primate intestinal tract M. G. BRYANT AND S. R. BLOOM From the Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London SUMMARY Reliable and specific radioimmunoassays have been developed for the gut hormones secretin, gastrin, cholecystokinin, pancreatic glucagon, VIP, GIP, motilin, and enteroglucagon. Using these assays, the relative pattern of distribution of the gut hormones has been determined using the same bowel extracts for all measurements. VIP occurred in high concentration in all regions of the bowel, whereas secretin, GIP, motilin, and CCK were predominantly localised in the proximal small intestine. Pancreatic glucagon was almost exclusively confined to the pancreas. Like VIP, enteroglucagon also exhibited a wide pattern of distribution but was maximal in the ileum. The acid ethanol extraction method that was used was found to be unsuitable for gastrin. On gel chromatography of the extracts, motilin and VIP eluted as single molecular species in identical position to the pure porcine peptides. CCK, pancreatic glucagon, enteroglucagon and GIP were all multiform. Over the last decade the development of radio- peptide throughout the primate intestinal tract immunoassays for the gut hormones has allowed using the same bowel extracts for all measurements. their quantitative measurement both in plasma and in tissue. Although this has prompted several investi- Methods http://gut.bmj.com/ gations to determine the normal distribution of these hormones in different species (Unger et al., 1961; EXTRACTION Bloom and Bryant, 1973; Reeder et al., 1973; The complete intestinal tract was removed after Rehfeld et al., 1975; Bloom et al., 1975; O'Dorisio brief anaesthesia from four healthy baboons and et al., 1976), no comprehensive study has been three monkeys (Macaca Iris) all of whom had been undertaken in the primate.
    [Show full text]
  • Secretin/Secretin Receptors
    JKVTAMand others Secretin and secretin receptor 52:3 T1–T14 Thematic Review evolution MOLECULAR EVOLUTION OF GPCRS Secretin/secretin receptors Correspondence Janice K V Tam, Leo T O Lee, Jun Jin and Billy K C Chow should be addressed to B K C Chow School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, Hong Kong Email [email protected] Abstract In mammals, secretin is a 27-amino acid peptide that was first studied in 1902 by Bayliss and Key Words Starling from the extracts of the jejunal mucosa for its ability to stimulate pancreatic " secretin secretion. To date, secretin has only been identified in tetrapods, with the earliest diverged " secretin receptor secretin found in frogs. Despite being the first hormone discovered, secretin’s evolutionary " evolution origin remains enigmatic, it shows moderate sequence identity in nonmammalian tetrapods " origin but is highly conserved in mammals. Current hypotheses suggest that although secretin has " divergence already emerged before the divergence of osteichthyans, it was lost in fish and retained only in land vertebrates. Nevertheless, the cognate receptor of secretin has been identified in both actinopterygian fish (zebrafish) and sarcopterygian fish (lungfish). However, the zebrafish secretin receptor was shown to be nonbioactive. Based on the present information that the earliest diverged bioactive secretin receptor was found in lungfish, and its ability to interact with both vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide potently suggested that secretin receptor was descended from a VPAC-like receptor gene before the Actinopterygii–Sarcopterygii split in the vertebrate lineage. Hence, Journal of Molecular Endocrinology secretin and secretin receptor have gone through independent evolutionary trajectories despite their concurrent emergence post-2R.
    [Show full text]
  • Inhibits Dopamine and Norepinephrine Release in the Hypothalamus
    European Journal of Pharmacology 519 (2005) 48 – 51 www.elsevier.com/locate/ejphar Peptide YY (3–36) inhibits dopamine and norepinephrine release in the hypothalamus Luigi Brunetti, Giustino Orlando, Claudio Ferrante, Annalisa Chiavaroli, Michele Vacca * Department of Drug Sciences, G. D’Annunzio University, School of Pharmacy, via dei Vestini, 66013 Chieti, Italy Received 1 June 2005; accepted 8 July 2005 Available online 10 August 2005 Abstract Peptide YY (1–36) and peptide YY (3–36) are gut-derived hormones which are involved in feeding control in the hypothalamus. The hypothalamic mechanisms of feeding have been shown to be modulated by aminergic neurotransmitters, which could mediate the anorectic or orexigenic effects of neuropeptides and hormones. We have investigated the role of peptide YY (1–36) and peptide YY (3– 36) on dopamine, norepinephrine, and serotonin release from hypothalamic synaptosomes in vitro. We found that peptide YY (3–36) inhibited depolarization-induced dopamine and norepinephrine release, leaving unaffected serotonin release, while peptide YY (1–36) did not modify either basal or stimulated amine release. We can hypothesize that the effects of peptide YY (3–36) could be mediated by inhibited hypothalamic dopamine and norepinephrine release, which could partially account for the anorectic activity of the peptide. On the other hand, peptide YY (1–36), which has a feeding stimulatory role, does not affect aminergic neurotransmission in the hypothalamus. D 2005 Elsevier B.V. All rights reserved. Keywords: Peptide YY; Hypothalamus; Dopamine; Norepinephrine; Serotonin 1. Introduction 2003). On the contrary, peptide YY (1–36) administration into cerebral ventricles (Clark et al., 1987), hypothalamic Peptide YY is a gastrointestinal hormone mainly secreted paraventricular nucleus and hippocampus (Stanley et al., by L cells of the distal small bowel and colon.
    [Show full text]
  • The Regulation of Circulating Ghrelin – with Recent Updates from Cell-Based Assays
    Endocrine Journal 2015, 62 (2), 107-122 REVIEW The regulation of circulating ghrelin – with recent updates from cell-based assays Hiroshi Iwakura1), Kenji Kangawa1), 2) and Kazuwa Nakao1) 1) Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan 2) National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan Abstract. Ghrelin is a stomach-derived orexigenic hormone with a wide range of physiological functions. Elucidation of the regulation of the circulating ghrelin level would lead to a better understanding of appetite control in body energy homeostasis. Earlier studies revealed that circulating ghrelin levels are under the control of both acute and chronic energy status: at the acute scale, ghrelin levels are increased by fasting and decreased by feeding, whereas at the chronic scale, they are high in obese subjects and low in lean subjects. Subsequent studies revealed that nutrients, hormones, or neural activities can influence circulating ghrelin levels in vivo. Recently developed in vitro assay systems for ghrelin secretion can assess whether and how individual factors affect ghrelin secretion from cells. In this review, on the basis of numerous human, animal, and cell-based studies, we summarize current knowledge on the regulation of circulating ghrelin levels and enumerate the factors that influence ghrelin levels. Key words: Ghrelin GHRELIN is a 28-amino-acid peptide hormone [1], on ghrelin secretion. The generation of ghrelin-produc- originally identified from the rat stomach as a natu- ing cell lines [29, 30] and FACS-based isolation of flu- ral ligand for growth hormone secretagogue receptor orescently tagged ghrelin-producing cells [30-32] have (GHS-R) [2].
    [Show full text]
  • Coexistence with Vasopressin and Corticotropin-Releasing Factor in Cells of the Rat Hypothalamic Paraventricular Nucleus
    Proc. Nati. Acad. Sci. USA Vol. 83, pp. 3510-3512, May 1986 Neurobiology Role of cholecystokinin in corticotropin release: Coexistence with vasopressin and corticotropin-releasing factor in cells of the rat hypothalamic paraventricular nucleus (neuroendocrinology/neuropeptides/corticotropin regulation) EVA MEZEY*, TERRY D. REISINE*, LANA SKIRBOLLt, MARGERY BEINFELDt, AND J6ZSEF Z. KIss*§ *Laboratory of Cell Biology and tClinical Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892; and tDepartment of Pharmacology, St. Louis University, School of Medicine, St. Louis, MO 63104 Communicated by J. Szentdgothai, December 18, 1985 ABSTRACT Cholecystokinin-8 (CCK8)-containing cell gelatin-coated slides. For details of the immunofluorescent bodies in the parvocellular region of the rat paraventricular staining, see Hokfelt et al. (15). Briefly, the brains were nucleus (PVN) contain vasopressin and corticotropin-releasing postfixed for 90 min, washed overnight, and sectioned in a factor (CRF). The CCK8 and vasopressin in these cells can cryostat. The 5-,um-thick sections were incubated with pri- readily be visualized in adrenalectomized, but not in sham- mary antibodies [a mixture of a rabbit polyclonal anti-CCK operated animals. Furthermore, CCK8 levels as measured by antiserum and a mouse monoclonal anti-vasopressin-neuro- RIA change in the PVN and in the median eminence in response physin (VP-NP) antibody, both at final dilution of 1:500] in to adrenalectomy. CCK8 has a stimulatory effect on cortico- 10% normal goat serum, 0.6% Triton X-100, and PBS. The tropin (ACTH) release from primary cultures of the anterior sections were incubated for 2 hr at room temperature fol- pituitary. This stimulation is additive with that produced by lowed by an overnight incubation at 4°C.
    [Show full text]
  • Endocrine Factors in the Modulation of Food Intake
    ploc. Nutr. SOC.(1978), 37, 301 301 Endocrine factors in the modulation of food intake By G. A. BRAY,Department of Medicine, UCLA School of Medicine, Harbor General Hospital Campus, 1000 West Carson Street, Torrance, CalifM.nia 90509 USA Food intake is controlled by multiple factors. Such a state of affairs has obvious advantages in assuring back-up control mechanisms should one or another of the systems become damaged or non-functional. This redundancy in control mechanisms is manifested by the fact that both humoral and metabolic messages are integrated with neural systems modulating the cyclic events of initiation, ingestion and termination of eating. For the present discussion, however, I shall focus on the putative hormonal factors which might be involved in regulation of food intake as though they were operating independently of messages derived from food nutrients or from the neural substrate and internal homeostatic mechanisms which are obviously also playing a role. Four groups of endocrine factors will be considered: peptide hormones arising from the gastrointestinal tract ; pancreatic hormones; steroid hormones arising from the gonads and/or adrenal; and thyroid hormones. Intestinal hormones and the regulation of food intake Since foods which enter the body are absorbed across the intestine, it is reasonable to suppose that gastrointestinal hormones, might play a major role in regulation of food intake, especially in the termination of a meal. This is not a new idea since an important role for the gastrointestinal tract was postulated more than 50 years ago by Carlson (1912)and by Canhon & Washburn (1912). Several gastrointestinal hormones have been identified and isolated.
    [Show full text]