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Cross-talk between insulin and serotonin signaling in the brain : Involvement of the PI3K/Akt pathway and behavioral consequences in models of insulin resistance Ioannis Papazoglou To cite this version: Ioannis Papazoglou. Cross-talk between insulin and serotonin signaling in the brain : Involvement of the PI3K/Akt pathway and behavioral consequences in models of insulin resistance. Agricultural sciences. Université Paris Sud - Paris XI, 2013. English. NNT : 2013PA11T039. tel-01171549 HAL Id: tel-01171549 https://tel.archives-ouvertes.fr/tel-01171549 Submitted on 5 Jul 2015 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. UNIVERSITÉ PARIS-SUD ÉCOLE DOCTORALE : "Signalisations et Réseaux intégratifs en Biologie" Laboratoire de Neuroendocrinologie Moléculaire de la Prise Alimentaire DISCIPLINE : Neuroendocrinologie THÈSE DE DOCTORAT Soutenue le 4 juillet 2013 par Ioannis Papazoglou “Cross-talk between insulin and serotonin signaling in the brain: Involvement of the PI3K/Akt pathway and behavioral consequences in models of insulin resistance” “Dialogue entre les voies de signalisation de l’insuline et de la sérotonine dans le cerveau: Implication de la voie PI3K/Akt et conséquences comportementales dans des modèles d’insulino-résistance” Directeur de Thèse Prof. Mohammed Taouis Université Paris-Sud Composition du jury: Présidente Prof. Anne Mantel Université Paris-Sud Rapporteurs : Prof. Serguei Fetissov Université de Rouen Dr. Michèle Guerre-Millo Centre de recherche des Cordeliers Examinateurs : Dr. Xavier Fioramonti Université de Bourgogne Dr. Ralf Jockers Institut Cochin Dr. Raymond Mongeau Université Pierre et Marie Curie Dr. Claire-Marie Vacher Université Paris-Sud Remerciements Je tiens tout d’abord à exprimer toute ma gratitude au Prof. Mohammed Taouis, Directeur du Laboratoire de « Neuroendocrinologie Moléculaire de la Prise Alimentaire », pour avoir accepté de diriger cette thèse. Je lui suis particulièrement reconnaissant de m’avoir guidé, soutenu et, au besoin, remotivé tout au long de ce travail doctoral. Ma reconnaissance va également au Dr. Gerozissis pour m’avoir accepté en thèse. Je remercie le Dr. Claire-Marie Vacher, sans qui la réalisation de la dernière partie du programme de cette thèse et son aboutissement n’auraient sans doute pas été possibles. J’ai pu apprécier sa disponibilité, sa pédagogie et sa gentillesse. C’est grâce à elle que je suis devenu le scientifique que je suis aujourd’hui. Je remercie le Prof. Anne Mantel pour avoir accepté d’être Présidente de mon jury de thèse. Je tiens à remercier le Prof. Serguei Fetissov et le Dr. Michèle Guerre-Millo pour m’avoir fait l’honneur et le plaisir d’évaluer et de critiquer ce travail malgré les courts délais que nous avons sollicités. J’adresse également tous mes remerciements aux examinateurs de cette thèse, les Drs. Xavier Fioramonti, Ralf Jockers et Raymond Mongeau pour avoir accepté de participer au jury de cette thèse et pour l’intérêt qu’ils ont porté à ces travaux. Je remercie enfin tous les membres, présents et passés, du laboratoire de « Neuroendocrinologie Moléculaire de la Prise Alimentaire » et du « Vekrellis Lab, Basic Neurosciences» pour leur amitié et collaboration pendant cette thèse. Publications Xu J., Xilouri M., Bruban J., Shioi J., Shao Z., Papazoglou I., Vekrellis K., Robakis N.K. (2011). Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging. 32(12):2326.e5-16. (see Annex 1) Papazoglou I., Berthou F., Vicaire N., Rouch C., Markaki E.M., Bailbe D., Portha B., Taouis M., Gerozissis K. (2012). Alteration of hypothalamic insulin signaling in a type 2 diabetes model associated with a defect in the serotonergic system. Mol Cell Endocrinol. 350(1):136-44. Papazoglou I., Jean A., Aubourg A., Gertler A., Taouis M., Vacher C.M. High fat diet induces a reversible depressive like behavior in rats, associated with a down-regulation of the PI3K/Akt/GSK3β pathway in the dentate gyrus. (in preparation) Communications Papazoglou I., Vicaire N., Berthou F., Gerozissis K. and Taouis M. (2010) Molecular mechanisms involved in brain Insulin signaling associated with metabolic and related dysfunctions. Journée de l’école doctorale "Signalisations et Réseaux intégratifs en Biologie", Faculté de Médecine Paris Sud, 28 May 2010, Paris, France Gerozissis K., Berthou F., Rouch C., Vicaire N., Papazoglou I., Bailbe D., Portha B., Taouis M. (2010) Reduced hypothalamic insulin receptor expression and insulin-dependent Akt phosphorylation in a type 2 diabetes model associated with a defect in the serotonergic system. 46th EASD Meeting, 20-24 September 2010, Stockholm, Sweden. Papazoglou I., Vicaire N., Berthou F., Gerozissis K. Taouis M. (2010) Molecular mechanisms involved in brain Insulin signaling associated with metabolic and related dysfunctions. “Neuroscience Days” Research Meeting of the Hellenic Society for Neuroscience, 1-2 October 2010, Athens, Greece. Papazoglou I., Vicaire N., Gerozissis K. Taouis M. (2012) Serotonin-Insulin signaling cross-talk in a human neuronal cell line. 8th FENS Forum of Neuroscience, 14-18 July 2012, Barcelona, Spain. Table of contents Introduction 1 1. Type 2 Diabetes, Obesity and Depression 1 1.1. Type 2 Diabetes Mellitus (T2D) 1 1.2. Obesity 2 1.3. Depression (Major Depressive Disorder) 2 1.4. Type 2 Diabetes, Obesity and Depression 3 2. Insulin 4 2.1. General 4 2.2. Production and Secretion 4 2.3. Degradation 4 2.4. Gene, Biosynthesis and structure 5 2.5. Insulin Signaling 6 2.5.1. Insulin Receptor (IR) 6 2.5.2. Substrates 8 a. Insulin Receptor Substrates (IRS) 8 b. Src-homology-2-containing proteins (Shc) 9 c. Other substrates and interacting proteins 9 2.5.3. Negative regulators of Insulin Signaling 10 a. Protein tyrosine phosphatase 1B (PTP1B) 10 b. Suppressor of cytokine signaling-3 (SOCS3) 10 2.6. Actions 12 2.6.1. Periphery 12 a. Liver 12 b. Muscle 12 c. Adipose tissue 13 2.6.2. Central nervous system 13 a. Insulin Receptor and signaling in the brain 13 b. Hypothalamus 14 i. The arcuate nucleus (ARC) 14 ii. The ventromedial nucleus (VMN) 16 c. Hippocampus 17 d. Insulin, Blood Brain Barrier (BBB) and glucose uptake 18 2.7. Insulin Resistance 18 3. Serotonin (5-HT) 19 3.1. General 19 3.2. Brain Serotonin 19 3.3. Production and secretion 19 3.4. Biosynthesis and structure 21 3.5. Degradation and uptake 22 3.6. Serotonin signaling 22 3.6.1. Serotonin Receptors 22 a. Class 1 22 b. Class 2 23 c. Class 3 24 d. Class 4-7 25 3.6.2. Activation of PI3K/Akt pathway by 5-HT 27 3.7. Functions of 5-HT in the Central Nervous System 27 3.7.1. Hypothalamic regulation of food intake 27 a. Arcuate nucleus (ARC) 28 i. 5-HT2C 28 ii. 5-HT1B 29 iii. 5-HT1A, 5-HT2B 29 iv. 5-HT1F 29 b. Ventromedial nucleus (VMN) 30 3.7.2. Hippocampal action of 5-HT and depression 30 a. The serotonin deficiency hypothesis of depression 30 b. 5-HT innervation of hippocampal neurons 31 c. Hippocampal 5-HT signaling and depression 32 4. Leptin 35 4.1. General 35 4.2. Production, Secretion and Degradation 35 4.3. Gene, Biosynthesis and structure 36 4.4. Leptin Signaling 36 4.4.1. Leptin Receptor (LepR/ObR) 36 4.4.2. Substrates 37 a. Janus kinase 2 (JAK2) 37 b. Signal transducer and activator of transcription 3/5 (STAT3/5) 38 c. SHP2 38 d. Src family kinases (SFKs) 38 e. SH2B 38 4.4.3. Leptin Signaling Negative Regulation 39 a. Suppressor of cytokine signaling-3 (SOCS3) 39 b. Protein tyrosine phosphatase 1-B (PTP1B) 40 c. T cell protein tyrosine phosphatase (TC-PTP) 40 d. Receptor protein tyrosine phosphatase epsilon (RPTPe) 40 4.4.4. Actions 41 a. Periphery 41 b. Central nervous system 41 i. Hypothalamus 42 ii. Hippocampus 42 4.5. Leptin Resistance 44 5. The PI3K/Akt signaling pathway 45 5.1. General 45 5.2. The phosphatidylinositol 3-kinases 45 5.2.1. Class I PI3Ks 46 a. Class IA 46 b. Class IB 48 5.2.2. Class II PI3Ks 48 5.2.3. Class III PI3Ks 49 5.3. Phosphoinositides 50 5.4. Negative regulation of PI3Ks 51 5.4.1. Phosphatase and tensin homologue – PTEN 51 5.4.2. Inositol polyphosphate 4- phosphatase – INPP4 52 5.4.3. Inositol polyphosphate 5- phosphatases (5-ptases) 52 5.5. Phosphoinositide dependent protein kinases 53 5.5.1. Akt/PKB protein kinase 53 5.5.2. GSK3 protein kinase 56 Results 57 Article 1 58 Article 2 67 Discussion 100 Conclusion 110 Annexes 113 Annex 1 114 Annex 2 127 References 131 List of Abbreviations 5-HIAA 5-hydroxyindoleacetic acid 5-HT 5-Hydroxytryptamine (=serotonin) 8-OH-DPAT 8-hydroxy-N,N-dipropyl-2-aminotetralin Aa Amino-acid AC Adenylate cyclase Agrp Agouti-related protein AMPA α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid AMPK 5'-AMP-activated protein kinase aPKC Atypical protein kinase C ARC Arcuate nucleus ATM Ataxia telangiectasia mutant BAD Bcl-2-associated death promoter BBB Blood Brain Barrier BMI Body Mass Index C3G Guanine nucleotide exchange factor CA1-3 Ammon’s Horn (Cornu Ammonis) 1-3 cAMP. Cyclic Adenosine monophosphate Casp9 Caspase 9 Cbl Ecotropic retroviral transforming sequence homologue cDNA complementary DNA CHR2 Cytokine homology regions 2 CNS Central
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  • The Roles of Peripheral Serotonin in Metabolic Homeostasis ⇑ Rabih El-Merahbi, Mona Löffler, Alexander Mayer, Grzegorz Sumara

    The Roles of Peripheral Serotonin in Metabolic Homeostasis ⇑ Rabih El-Merahbi, Mona Löffler, Alexander Mayer, Grzegorz Sumara

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 589 (2015) 1728–1734 journal homepage: www.FEBSLetters.org Review The roles of peripheral serotonin in metabolic homeostasis ⇑ Rabih El-Merahbi, Mona Löffler, Alexander Mayer, Grzegorz Sumara Rudolf Virchow Center for Experimental Biomedicine University of Würzburg, Josef-Schneider-Str. 2, Haus D15, D-97080 Würzburg, Germany article info abstract Article history: Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Received 17 April 2015 Among a plethora of hormones regulating metabolism, serotonin presents a number of unique fea- Revised 26 May 2015 tures. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it Accepted 30 May 2015 acts as a neurotransmitter and in the periphery it can act as a hormone, auto- and/or paracrine fac- Available online 9 June 2015 tor, or intracellular signaling molecule. Serotonin does not cross the blood–brain barrier; therefore Edited by Ned Mantei the two major pools of this bioamine remain separated. Although 95% of serotonin is produced in the periphery, its functions have been ignored until recently. Here we review the impact of the peripheral serotonin on the regulation of function of the organs involved in glucose and lipid Keywords: Peripheral serotonin homeostasis. Pancreatic b cell Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Hepatocyte Adipocyte Diabetes 1. Introduction and it became clear in recent years that it regulates function of multiple aspects of physiology.