DOCSLIB.ORG

I REGULATION of ARCUATE NUCLEUS KISSPEPTIN/NEUROKININ B and GONADOTROPIN-RELEASING HORMONE DURING NEGATIVE ENERGY BALANCE By

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
I REGULATION of ARCUATE NUCLEUS KISSPEPTIN/NEUROKININ B and GONADOTROPIN-RELEASING HORMONE DURING NEGATIVE ENERGY BALANCE By REGULATION OF ARCUATE NUCLEUS KISSPEPTIN/NEUROKININ B AND GONADOTROPIN-RELEASING HORMONE DURING NEGATIVE ENERGY BALANCE By Cadence True A DISSERTATION Presented to the Division of Neuroscience and Oregon Health & Science University School of Medicine in partial fulfillment of the requirement of the degree of Doctor of Philosophy August 2012 i Table of Contents Chapter 1 - INTRODUCTION 1 1. Integration of metabolic and reproductive function 2 2. The hypothalamic-pituitary-gonadal axis 4 3. Kisspeptin as a critical signal for GnRH regulation 7 3.1 Arcuate nucleus Kiss1 cells coexpress Neurokinin B and Dynorphin 10 3.2 Regulation of the Kiss1 populations by estradiol 12 3.3 Kiss1 in negative energy balance 16 4. Metabolic signals of negative energy balance 17 4.1 Insulin 18 4.2 Leptin 20 4.2 Hypothalamic neuropeptides involved in regulating energy homeostasis and reproduction 24 5. Animal models of negative energy balance 28 5.1 Lactation as a model of negative energy balance 30 5.2 Undernutrition models of negative energy balance 35 6. The requirement of estradiol for negative energy balance-induced GnRH inhibition 37 7. Statement of purpose 40 AIMS OF THE THESIS AND APPROACH 41 Chapter 2 - Characterisation of Arcuate Nucleus Kisspeptin/Neurokinin B Neuronal Projections and Regulation during Lactation in the Rat 43 ABSTRACT 44 INTRODUCTION 45 MATERIALS AND METHODS 47 RESULTS 54 DISCUSSION 58 CHAPTER 3 -Leptin is not the critical signal for kisspeptin or luteinizing hormone restoration during exit from negative energy balance 72 ABSTRACT 73 INTRODUCTION 74 MATERIALS AND METHODS 76 RESULTS 82 DISCUSSION 86 Chapter 4- The role of cocaine- and amphetamine-regulated transcript in metabolically-driven GnRH inhibition 103 ABSTRACT 104 INTRODUCTION 105 MATERIALS AND METHODS 107 RESULTS 111 DISCUSSION 114 ii Chapter 5- DISCUSSION 129 1. Beyond leptin: emerging candidates for the integration of metabolic and reproductive function 130 1.2 Negative energy balance-induced acyclicity and hypoleptinemia 132 1.3 Inhibition of kisspeptin as a central mechanism of GnRH inhibition 134 1.4 Regulation of neurokinin B and dynorphin as a central mechanism of GnRH inhibition 135 1.5 Gonadotropin-inhibitory hormone 137 1.6 Alarin 139 1.7 Brainstem glucose-sensing populations 140 1.8. Adiponectin 144 1.9 The hypothalamic-pituitary-adrenal axis 145 2. Discrepancies in studies investigating Kiss1 projections 149 2.1 Dual-label immunohistochemistry for projection mapping 149 2.2 Kiss1 regulation of GnRH at the median eminence 152 3. Interpreting incongruity between protein and mRNA levels 153 4. Similarities between Kiss1 and CART populations for GnRH regulation 154 4.1. Kiss1 and CART involvement in estradiol-mediated GnRH inhibition during CR 158 5. Conclusions 159 REFERENCES 166 iii Figures Figure 1: Colocalisation of Kiss1 and NKB in the ARH. .......................................................................................... 65 Figure 2. Kiss1 and NKB fiber distribution in the ME. ........................................................................................... 66 Figure 3. NKB immunoreactivity in the ARH and ME using NiDAB secondary detection. ...................................... 67 Figure 4. Computer assisted line drawings of Kiss1/NKB-ir rostral fiber projections from the ARH. ..................... 68 Figure 5. Colocalized Kiss1/NKB-ir fibers at the level of the PVa, AVPV and NDB. ................................................ 69 Figure 6. ARH Kiss1 and NKB immunohistochemistry during diestrus and lactation............................................. 70 Figure 7. Kiss1 peptide and mRNA in the AVPV during diestrus and lactation. ..................................................... 71 Figure 1. Body composition and serum leptin and LH levels in response to 40% CR. ............................................ 94 Figure 2. Hypothalamic mRNA expression in response to 40% CR. ....................................................................... 95 Figure 3. Body composition and serum leptin and LH levels in response to 50% CR. ............................................ 96 Figure 4. Hypothalamic mRNA expression in response to 50% CR. ....................................................................... 97 Figure 5. Changes in body weight, serum leptin, serum LH, and ARH Kiss1 mRNA levels in response to the 48- hour fast. ..................................................................................................................................................... 98 Figure 6. pSTAT3 and Kiss1 immunohistochemistry following acute pharmacological leptin administration. ...... 99 Supplemental Figure 1. ARH pSTAT3 immunohistochemistry in fasted animals following leptin minipump implantation. ............................................................................................................................................. 100 Supplemental Figure 2. Daily changes in body weight and food intake during 40% CR. ..................................... 101 Supplemental Figure 3. ARH feeding neuropeptide mRNA levels in response to 40% and 50% CR. ................... 102 Figure 1. Arcuate nucleus CART protein and mRNA levels during caloric restriction (CR). A) Confocal photomicrograph of immunohistochemistry for CART protein (Phoenix antibody, H-003-62) in the arcuate nucleus (ARH, location denoted by dotted line) in ab libitum fed and 50% CR animals (100 µM scale bar provided). Quantification of ARH CART cell numbers is provided in the bar graph. B) Dark field silver grain photomicrograph of in situ hybridization for 35S-CART mRNA probe. Quantification of ARH CART mRNA integrated intensities provided in the histogram. Sample group size is given within eachnhistogram. 3V abbreviation for third ventricle. ................................................................................................................ 120 Figure 2. Dorsomedial hypothalamus CART protein and mRNA levels during caloric restriction (CR). A) Confocal photomicrograph of immunohistochemistry for CART protein in the dorsomedial hypothalamus (DMH, location denoted by dotted line) in ab libitum fed and 50% CR animals (100 µM scale bar provided). Quantification of DMH CART cell numbers is provided in the bar graph. B) Dark field silver grain photomicrograph of in situ hybridization for 35S-CART mRNA probe. Quantification of DMH CART mRNA integrated intensities provided in the histogram. Sample group size is given within each histogram. 3V abbreviation for third ventricle. ................................................................................................................ 121 Figure 3. Anteroventral periventricular nucleus CART protein and mRNA levels during caloric restriction (CR). A) Confocal photomicrograph of immunohistochemistry for CART protein in the AVPV (location denoted by dotted line) in ab libitum fed and 50% CR animals (100 µM scale bar provided). Quantification of AVPV CART cell numbers is provided in the bar graph. B) Dark field silver grain photomicrograph of in situ hybridization for 35S-CART mRNA probe. Quantification of AVPV CART mRNA integrated intensities provided in the histogram. Sample group size is given within each histogram. Abbreviations 3V, third ventricle and OC, optic chiasm. ................................................................................................................. 122 Figure 4. Arcuate nucleus CART protein and mRNA levels during lactation. ....................................................... 123 Figure 5. Dorsomedial hypothalamus nucleus CART protein and mRNA levels during lactation. ........................ 124 Figure 6. Anteroventral periventricular nucleus CART protein and mRNA levels during lactation. A) Confocal photomicrograph of immunohistochemistry for CART protein in the AVPV (location denoted by dotted line) during virgin control and lactation conditions (100 µM scale bar provided). Quantification of AVPV CART cell numbers is provided in the bar graph. B) Dark field silver grain photomicrograph of in situ iv hybridization for 35S-CART mRNA probe. Quantification of AVPV CART mRNA integrated intensities provided in the histogram. Sample group size is given within each histogram. 3V abbreviation for third ventricle. ................................................................................................................................................... 125 Figure 7. Distribution of CART and Kiss1 cells in the periventricular region and AVPV during lactation. Photomicrographs of immunohistochemistry for CART-ir (green) and Kiss1-ir (red) in the rostral............. 126 Figure 8. CART close appositions onto GnRH cells near the AVPV and ARH and AVPV Kiss1 cells. Photomicrograph of triple-label immunohistochemistry for CART (green), α-MSH (blue) and either GnRH ........................... 127 Figure 9. Working model of the role of CART and Kiss1 for negative energy balance-induced GnRH inhibition. CART populations (green) in the ARH and AVPV nucleus are inhibited (red downward arrow) ................. 128 Figure 1. Close appositions of brainstem catecholamine fibers on arcuate nucleus (ARH) NKB and AVPV Kiss1cells. .................................................................................................................................................. 164 Figure 2. Proposed schematic of negative energy balance-induced changes in reproductive and metabolic circuits contributing to GnRH inhibition. ..............................................................................................................
Load more

Recommended publications
  • Corticotropin-Releasing Hormone Physiology
    European Journal of Endocrinology (2006) 155 S71–S76 ISSN 0804-4643 Corticotropin-releasing hormone physiology Joseph A Majzoub Division of Endocrinology, Children’s Hospital Boston, Thomas Morgan Rotch Professor of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA (Correspondence should be addressed to J A Majzoub; Email: [email protected]) Abstract Corticotropin-releasing hormone (CRH), also known as corticotropin-releasing factor, is a highly conserved peptide hormone comprising 41 amino acid residues. Its name derives from its role in the anterior pituitary, where it mediates the release of corticotropin (ACTH) leading to the release of adrenocortical steroids. CRH is the major hypothalamic activator of the hypothalamic–pituitary– adrenal (HPA)axis. Major functions of the HPAinclude: (i) influencing fetal development of major organ systems including lung, liver, and gut, (ii) metabolic functions, including the maintenance of normal blood glucose levels during the fasting state via glycogenolysis and gluconeogenesis, (iii) modulation of immune function, and (iv) maintenance of cardiovascular tone. In addition, CRH, acting both directly and via the HPA, has a role in regulating several neuroendocrine functions including behavior, food intake, reproduction, growth, immune function, and autonomic function. CRH has been localized to the paraventricular nucleus (PVN) of the hypothalamus, which projects to the median eminence and other hypothalamic and midbrain targets. The CRH gene is composed of two exons. The CRH promoter contains a cAMP-response element, and the intron contains a restrictive element-1/neuron restrictive silencing element (RE-1/NRSE) sequence. Recently, a family of CRH-related peptides, termed the urocortins, has been identified.
    [Show full text]
  • Expression of Urocortin and Corticotropin-Releasing Hormone Receptors in the Horse Thyroid Gland
    Cell Tissue Res DOI 10.1007/s00441-012-1450-4 REGULAR ARTICLE Expression of urocortin and corticotropin-releasing hormone receptors in the horse thyroid gland Caterina Squillacioti & Adriana De Luca & Sabrina Alì & Salvatore Paino & Giovanna Liguori & Nicola Mirabella Received: 11 January 2012 /Accepted: 3 May 2012 # Springer-Verlag 2012 Abstract Urocortin (UCN) is a 40-amino-acid peptide and UCN, CRHR1 and CRHR2 and that UCN plays a role in a member of the corticotropin-releasing hormone (CRH) the regulation of thyroid physiological functions through a family, which includes CRH, urotensin I, sauvagine, paracrine mechanism. UCN2 and UCN3. The biological actions of CRH family peptides are mediated via two types of G-protein-coupled Keywords Follicular cells . C-cells . RT-PCR . receptors, namely CRH type 1 receptor (CRHR1) and CRH Immunohistochemistry . Horse type 2 receptor (CRHR2). The biological effects of these peptides are mediated and modulated not only by CRH receptors but also via a highly conserved CRH-binding Introduction protein (CRHBP). Our aim was to investigate the expression of UCN, CRHR1, CRHR2 and CRHBP by immunohisto- Urocortin (UCN) is a peptide of 40 amino acids and is a chemistry, Western blot and reverse transcription with the member of the corticotropin-releasing hormone (CRH) fam- polymerase chain reaction (RT-PCR) in the horse thyroid ily, which includes CRH, urotensin I, sauvagine, UCN2 and gland. The results showed that UCN, CRHR1 and CRHR2 UCN3. Vaughan et al. (1995) were the first to identify UCN, were expressed in the thyroid gland, whereas CRHBP was which exhibits 45% homology to CRH (Latchman 2002; not expressed.
    [Show full text]
  • Searching for Novel Peptide Hormones in the Human Genome Olivier Mirabeau
    Searching for novel peptide hormones in the human genome Olivier Mirabeau To cite this version: Olivier Mirabeau. Searching for novel peptide hormones in the human genome. Life Sciences [q-bio]. Université Montpellier II - Sciences et Techniques du Languedoc, 2008. English. tel-00340710 HAL Id: tel-00340710 https://tel.archives-ouvertes.fr/tel-00340710 Submitted on 21 Nov 2008 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE MONTPELLIER II SCIENCES ET TECHNIQUES DU LANGUEDOC THESE pour obtenir le grade de DOCTEUR DE L'UNIVERSITE MONTPELLIER II Discipline : Biologie Informatique Ecole Doctorale : Sciences chimiques et biologiques pour la santé Formation doctorale : Biologie-Santé Recherche de nouvelles hormones peptidiques codées par le génome humain par Olivier Mirabeau présentée et soutenue publiquement le 30 janvier 2008 JURY M. Hubert Vaudry Rapporteur M. Jean-Philippe Vert Rapporteur Mme Nadia Rosenthal Examinatrice M. Jean Martinez Président M. Olivier Gascuel Directeur M. Cornelius Gross Examinateur Résumé Résumé Cette thèse porte sur la découverte de gènes humains non caractérisés codant pour des précurseurs à hormones peptidiques. Les hormones peptidiques (PH) ont un rôle important dans la plupart des processus physiologiques du corps humain.
    [Show full text]
  • Corticotropin-Releasing Factor, Neuroplasticity (Sensitization), and Alcoholism
    COMMENTARY Corticotropin-releasing factor, neuroplasticity (sensitization), and alcoholism George F. Koob* Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037 ensitization is a ubiquitous bio- logical phenomenon that has a role in the neuroadaptation of many different functions, from Slearning and memory to stress respon- sivity. Historically, a specific form of sensitization termed psychomotor sensi- tization (mistermed in my view as ‘‘be- havioral sensitization’’) is induced by repeated administration of drugs of abuse and has been linked to the neuro- adaptive changes associated with increased drug-seeking behavior associ- Fig. 1. CNS actions relevant to alcohol-induced psychomotor sensitization. CRF is a neuropeptide in the ated with addiction. Largely observed brain that controls autonomic, hormonal, and behavioral responses to stressors. New data show that CRF with psychostimulant drugs, also has a role in the neuroplasticity associated with addiction. The present study extends the role of CRF psychomotor sensitization has been con- to the psychomotor sensitization associated with repeated administration of alcohol. The hypothalamic- sidered a model for the increased pituitary-adrenal responses produced by CRF appear to be more involved in the acquisition of sensitiza- incentive salience contributing to the tion, whereas extrahypothalamic CRF systems, likely to be in structures such as the amygdala, appear to increased motivation to seek drugs in be important for the expression of sensitization. These results, combined with previous studies on the role of CRF in the development of alcohol dependence, suggest a key role for CRF in the neuroplasticity individuals with a previous history of associated with addiction.
    [Show full text]
  • Urocortin 2 Modulates Glucose Utilization and Insulin Sensitivity in Skeletal Muscle
    Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle Alon Chen*†, Bhawanjit Brar*, Cheol Soo Choi‡, David Rousso*, Joan Vaughan*, Yael Kuperman†, Shee Ne Kim‡, Cindy Donaldson*, Sean M. Smith*, Pauline Jamieson*, Chien Li*, Tim R. Nagy§, Gerald I. Shulman‡, Kuo-Fen Lee*, and Wylie Vale*¶ *Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037; †Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel; ‡Department of Internal Medicine and Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536; and §Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294 Contributed by Wylie Vale, August 28, 2006 Skeletal muscle is the principal tissue responsible for insulin- Results and Discussion stimulated glucose disposal and is a major site of peripheral insulin Generation of Ucn 2-Deficient Mice. To explore the physiological resistance. Urocortin 2 (Ucn 2), a member of the corticotropin- role of Ucn 2, we generated mice that are deficient in this releasing factor (CRF) family, and its cognate type 2 CRF receptor peptide. A genomic DNA clone containing Ucn 2 was isolated, (CRFR2) are highly expressed in skeletal muscle. To determine the and a targeting construct in which the full Ucn 2 coding sequence physiological role of Ucn 2, we generated mice that are deficient in was replaced with a neomycin-resistant gene cassette was gen- this peptide. Using glucose-tolerance tests (GTTs), insulin-tolerance erated (Fig. 1a). J1 ES cells were electroporated with the tests (ITTs), and hyperinsulinemic euglycemic glucose clamp stud- targeting construct and were selected as described in ref.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • Multi-Functionality of Proteins Involved in GPCR and G Protein Signaling: Making Sense of Structure–Function Continuum with In
    Cellular and Molecular Life Sciences (2019) 76:4461–4492 https://doi.org/10.1007/s00018-019-03276-1 Cellular andMolecular Life Sciences REVIEW Multi‑functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder‑based proteoforms Alexander V. Fonin1 · April L. Darling2 · Irina M. Kuznetsova1 · Konstantin K. Turoverov1,3 · Vladimir N. Uversky2,4 Received: 5 August 2019 / Revised: 5 August 2019 / Accepted: 12 August 2019 / Published online: 19 August 2019 © Springer Nature Switzerland AG 2019 Abstract GPCR–G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signal- ing cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand–GPCR and GPCR–G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defnes an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR–G protein system represents an illustrative example of the protein structure–function continuum, where structures of the involved proteins represent a complex mosaic of diferently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fne-tuned by various post-translational modifcations and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specifc partners.
    [Show full text]
  • Neuropeptide-Induced Contraction and Relaxation of the Mouse
    Proc. Natl. Acad. Sci. USA Vol. 81, pp. 625-629, January 1984 Physiological Sciences Neuropeptide-induced contraction and relaxation of the mouse anococcygeus muscle (neurohypophysial peptides/neurotensin/thyrotropin-releasing hormone/urotensin i/vasoactive intestinal polypeptide) ALAN GIBSON*, HOWARD A. BERNtt, MICHAEL GINSBURG*, AND JACK H. BOTTING* *Department of Pharmacology, Chelsea College, University of London, Manresa Road, London SW3 6LX, United Kingdom; and tDepartment of Zoology and Cancer Research Laboratory, University of California, Berkeley, CA 94720 Contributed by Howard A. Bern, September 26, 1983 ABSTRACT Isometric tension responses to neuropeptides fects of a wide range of neuropeptides on tone of the mouse were recorded from anococcygeus muscles isolated from male anococcygeus in vitro. mice. This smooth muscle tissue is innervated by inhibitory nonadrenergic, noncholinergic nerves that resemble, ultra- MATERIALS AND METHODS structurally, the peptidergic neurons of the gastrointestinal Male mice (LACA strain from A. Tuck & Son, Battles- tract; the physiological function of the anococcygeus is not bridge, Essex, U.K.; 25-35 g) were stunned and bled. Both known. Slow sustained contractions were produced by oxyto- anococcygeus muscles were dissected from the animal and cin (0.2-20 nM), [Arg8]vasopressin (0.4-200 nM), and [Arg]- set up in series, joined at the point of unification on the ven- vasotocin (0.4-100 nM); the mouse anococcygeus is, therefore, tral rectum, in 1-ml glass organ baths that contained Krebs one of the few examples of nonvascular smooth muscle from bicarbonate solution (mM: NaCl, 118.1; KCI, 4.7; MgSO4, male mammals to respond to low concentrations of oxytocin 1.0; KH2PO4, 1.2; CaCl2, 2.5; NaHCO3, 25.0; glucose, 11.1).
    [Show full text]
  • Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms
    Review Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms Melpomeni Fani 1,*, Petra Kolenc Peitl 2 and Irina Velikyan 3 1 Division of Radiopharmaceutical Chemistry, University Hospital of Basel, 4031 Basel, Switzerland; [email protected] 2 Department of Nuclear Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; [email protected] 3 Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden; [email protected] * Correspondence: [email protected]; Tel.: +41-61-556-58-91; Fax: +41-61-265-49-25 Academic Editor: Klaus Kopka Received: 7 February 2017; Accepted: 9 March 2017; Published: 15 March 2017 Abstract: Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon- Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists.
    [Show full text]
  • Download (750Kb)
    The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa. Artur Pałasz a, Małgorzata Janas-Kozik b, Amanda Borrow c, Oscar Arias-Carrión d , John J. Worthington e a Department of Histology, School of Medicine in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland b Department of Psychiatry and Psychotherapy, School of Medicine in Katowice, Medical University of Silesia, ul. Ziolowa 45/47 Katowice, 40-635, Poland c Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, 80523- 161, US d Unidad de Trastornos del Movimiento y Sueño, Hospital General Dr Manuel Gea Gonzalez, Mexico City, Mexico e Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK Abstract Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour.
    [Show full text]
  • Urocortin 2 Autocrine/Paracrine and Pharmacologic Effects to Activate AMP-Activated Protein Kinase in the Heart
    Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart Ji Lia, Dake Qib, Haiying Chengc, Xiaoyue Hub, Edward J. Millerd, Xiaohong Wub, Kerry S. Russellb, Nicole Mikushb, Jiasheng Zhangb, Lei Xiaoe, Robert S. Sherwinc, and Lawrence H. Youngb,1 aDepartment of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY 14214; bSection of Cardiovascular Medicine and cSection of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; dDepartment of Medicine, Boston University, Boston, MA 02118; and eUniversity of Florida Shands Cancer Center, Department of Anatomy and Cell Biology, College of Medicine, Gainesville, FL 32610 Edited* by Gerald I. Shulman, Howard Hughes Medical Institute and Yale University, New Haven, CT, and approved August 9, 2013 (received for review July 11, 2013) Urocortin 2 (Ucn2), a peptide of the corticotropin-releasing factor Ucn2 (5). Signaling pathways have substantial cross-talk, and (CRF) family, binds with high affinity to type 2 CRF receptors pharmacologic inhibitor studies suggest a possible association (CRFR2) on cardiomyocytes and confers protection against ische- between activation of PKCe and the energy-stress kinase AMP- mia/reperfusion. The mechanisms by which the Ucn2-CRFR2 axis activated protein kinase (AMPK) (10). AMPK is activated by mitigates against ischemia/reperfusion injury remain incompletely changes in cellular energetics, but its activity is also modulated
    [Show full text]
  • Neuropeptide Regulation of Signaling and Behavior in the BNST
    Mol. Cells 2015; 38(1): 1-13 http://dx.doi.org/10.14348/molcells.2015.2261 Molecules and Cells http://molcells.org Established in 1990G Neuropeptide Regulation of Signaling and Behavior in the BNST Thomas L. Kash*, Kristen E. Pleil, Catherine A. Marcinkiewcz, Emily G. Lowery-Gionta, Nicole Crowley, Christopher Mazzone, Jonathan Sugam, J. Andrew Hardaway, and Zoe A. McElligott Recent technical developments have transformed how neu- aversion related behaviors, however there is also evidence that roscientists can probe brain function. What was once it can regulate appetitive responses. Numerous pharmacologi- thought to be difficult and perhaps impossible, stimulating a cal studies targeting different peptide systems as well as single set of long range inputs among many, is now relative- monoaminergic systems have found that the BNST plays a key ly straight-forward using optogenetic approaches. This has role in anxiety. For example, the Davis group has found that provided an avalanche of data demonstrating causal roles CRF in the BNST can potently enhance anxiety (Walker et al., for circuits in a variety of behaviors. However, despite the 2009b) and the Hammack group has found that PACAP signal- critical role that neuropeptide signaling plays in the regula- ing can alter stress responses (Kocho-Schellenberg et al., tion of behavior and physiology of the brain, there have 2014; Lezak et al., 2014a; 2014b). In support of this, recent been remarkably few studies demonstrating how peptide findings from several groups using optogenetic approaches release is causally linked to behaviors. This is likely due to have shown the BNST plays a role in anxiety (Jennings et al., both the different time scale by which peptides act on and 2013a; Kim et al., 2013), however these manuscripts also the modulatory nature of their actions.
    [Show full text]