DOCSLIB.ORG

Shared Cerebral Metabolic Pathology in Non-Transgenic Animal Models of Alzheimer’S And… 233 Intracellularly (Mitochondria, the Target of Toxicity)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Shared Cerebral Metabolic Pathology in Non-Transgenic Animal Models of Alzheimer’S And… 233 Intracellularly (Mitochondria, the Target of Toxicity) Journal of Neural Transmission (2020) 127:231–250 https://doi.org/10.1007/s00702-020-02152-8 NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE Shared cerebral metabolic pathology in non‑transgenic animal models of Alzheimer’s and Parkinson’s disease Jelena Osmanovic Barilar1 · Ana Knezovic1 · Ana Babic Perhoc1 · Jan Homolak1 · Peter Riederer2,3 · Melita Salkovic‑Petrisic1,4 Received: 17 December 2019 / Accepted: 24 January 2020 / Published online: 6 February 2020 © The Author(s) 2020 Abstract Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the most common chronic neurodegenerative disorders, character- ized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and co- expression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/ PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder. Keywords Parkinson’s disease · Alzheimer’s disease · Non-transgenic animal models · Insulin resistant brain state · Cerebral glucose metabolism Introduction Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the most common chronic neurodegenerative disorders. PD is characterized by classic motor dysfunction symptoms due * Melita Salkovic-Petrisic largely to the loss of dopaminergic neurons in the substantia [email protected] nigra pars compacta (SNpc) and intracytoplasmic aggregates of the presynaptic protein α-synuclein (α-Syn) in formations 1 Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, 10 000 Zagreb, Croatia called Lewy bodies (Davie 2008). On the other hand, AD is characterized by cognitive decline due to neuronal loss 2 Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, in the hippocampus (HPC) and temporal cortex, associated Würzburg, Füchsleinstrasse 15, 97080 Würzburg, Germany with pathological accumulation of aggregates of amyloid 3 Department and Research Unit of Psychiatry, Institute beta protein (Aβ) which forms extracellular plaques, and of Clinical Research, University of Southern Denmark, hyperphosphorylated tau protein which forms intracellular Odense, Denmark neurofbrillary tangles (Ballard et al. 2011). However, in the 4 Institute of Fundamental Clinical and Translational late stage of PD, the majority of patients also manifest cog- Neuroscience, Research Centre of Excellence, Croatian nitive defcits and dementia (Caballol et al. 2007; Gratwicke Institute for Brain Research, University of Zagreb School et al. 2018), while motor symptoms which also include of Medicine, Salata 12, 10 000 Zagreb, Croatia Vol.:(0123456789)1 3 232 J. O. Barilar et al. parkinsonism are present in the majority of patients with end appearance in correlation with cognitive and motor symp- stage AD (O’Keefe et al. 1996; Ballard et al. 2011; Levin toms will be pointed out. 2019). Despite diferent phenotypes, AD and PD share some common pathological features, e.g. oxidative stress and neu- roinfammation (Han et al. 2018). Metabolic changes pre- Direct or indirect toxicity as a cause sented as insulin resistant brain state (IRBS) have recently of the central insulin‑related metabolic gained more and more attraction as the pathophysiological pathology core of AD (Hoyer 2004; Chen et al. 2014; Defelice and Ferreira 2002; de la Monte et al. 2014), particularly after the Chemically induced non-transgenic animal models of AD results of epidemiological studies demonstrating that type 2 and PD play an important role in defning critical disease- diabetes mellitus (DM) is a risk factor for AD (Santiago and related mechanisms. Peripheral or central application of dif- Potashkin 2013). However, some studies provided evidence ferent substances, sometimes even in diferent parts of the that IRBS is also occurring in PD patients (Athauda and brain (e.g. by intracerebroventricular [icv] or intrastriatal Foltynie 2016; Yang et al. 2018) and that DM is a risk fac- injection), with diferent mechanisms of action, results in tor for PD as well (Biosa et al. 2018). Consequently, clinical diferent clinical symptoms which mimic those predominant trials have been designed to test the therapeutic potential of in AD or PD patients. However, despite all these diferences, antidiabetic drugs, in particular intranasal insulin (Claxton these models also point to the common underlying molecular et al. 2015) and incretins (glucagon-like peptide-1 [GLP-1] mechanisms of neuronal dysfunction (e.g. neuroinfamma- analogues) in AD and PD patients (Athauda and Foltynie tion, mitochondrial dysfunction and oxidative stress) when 2016; Femminella and Edison 2014). AD and PD seem like neurons and surrounding microglia and astrocytes are in two streets going in parallel to the same direction called stress following damage induced frst by injection trauma neurodegeneration with some overlap in their paths, and and consequently by toxin-induced chemical reactions. It is the nature of this overlap and the point at which it starts in still not clear whether neuroinfammation is the driven force the course of their pathophysiology seem to be the crucial of neurodegenerative disorders or is it a consequence of the questions. metabolic dysfunction occurring earlier in the progression of The pathology in both AD and PD starts years before diseases (Yin 2016). Based on its chemical structure, strep- the frst clinical symptoms and is difcult to trace in living tozotocin (STZ) might play multiple roles as a nonspecifc humans, which is why animal PD and AD models are valu- cytotoxic compound which causes mitochondrial dysfunc- able tools. Although one should keep in mind that none of tion, oxidative stress and neuroinfammation, as well as a the animal models is able to fully recapitulate PD and AD selective metabolic toxin which causes damage to insulin- pathology and symptoms, they are currently the only tool producing/secreting and insulin receptor (IR)-expressing available to study the underlying pathophysiology mecha- cells (Correia et al. 2013; Eleazu et al. 2013). On the other nisms of these two diseases. Based on the involvement of side, 6-hydroxydopamine (6-OHDA) also demonstrates gene manipulation in designing of the models, they can be nonspecifc toxicity by causing oxidative and mitochondrial classifed in transgenic (genetic) and non-transgenic models damage and neuroinfammation, as well as selective toxicity generated by injection of diferent chemical, mainly neuro- to the dopaminergic neurons (Walsh et al. 2011). Despite of toxic compounds. Each group has advantages and disadvan- that, both e.g. STZ/AD and 6-OHDA/PD models seem to tages, but genetic models generally represent the early onset share IRBS and other insulin-related pathological features forms of familial AD and PD, while the prevailing majority to a certain extent. of AD and PD patients sufer from the sporadic and idi- opathic forms of these diseases, respectively, for which non- Parkinson’s disease models transgenic animal models are more appropriate. This review aims to point out the similarities and diferences in IRBS Although there are several neurotoxin-generated animal and related cerebral metabolic pathology between the non- models of PD, the two golden standards are rats treated with transgenic PD and AD animal models. The representative 6-OHDA, and mice (or primates) treated with 1-methyl- non-transgenic AD and PD models will be compared from 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Tieu 2011) a perspective of similarities in the intracellular mechanism which will be more closely elaborated in this review. and target(s) of the toxicity of the compounds used to con- struct the models as well as the principles of their selectiv- Molecular targets responsible for selective toxicity ity toward targeted neurons and non-neuronal cells. Finally, the alterations in insulin brain system and related interac- MPTP and 6-OHDA share the same molecular target both tion between insulinergic and dopaminergic transmission, at the cellular membrane (i.e. dopamine transporter [DAT], particularly regarding the time frame of AD/PD pathology a target for selectivity, but not the direct toxicity) and 1 3 Shared cerebral metabolic pathology in non-transgenic animal
Load more

Recommended publications
  • Effect of Hydrolyzable Tannins on Glucose-Transporter Expression and Their Bioavailability in Pig Small-Intestinal 3D Cell Model
    molecules Article Effect of Hydrolyzable Tannins on Glucose-Transporter Expression and Their Bioavailability in Pig Small-Intestinal 3D Cell Model Maksimiljan Brus 1 , Robert Frangež 2, Mario Gorenjak 3 , Petra Kotnik 4,5, Željko Knez 4,5 and Dejan Škorjanc 1,* 1 Faculty of Agriculture and Life Sciences, University of Maribor, Pivola 10, 2311 Hoˇce,Slovenia; [email protected] 2 Veterinary Faculty, Institute of Preclinical Sciences, University of Ljubljana, Gerbiˇceva60, 1000 Ljubljana, Slovenia; [email protected] 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia; [email protected] 4 Department of Chemistry, Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia; [email protected] (P.K.); [email protected] (Ž.K.) 5 Laboratory for Separation Processes and Product Design, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, 2000 Maribor, Slovenia * Correspondence: [email protected]; Tel.: +386-2-320-90-25 Abstract: Intestinal transepithelial transport of glucose is mediated by glucose transporters, and affects postprandial blood-glucose levels. This study investigates the effect of wood extracts rich in hydrolyzable tannins (HTs) that originated from sweet chestnut (Castanea sativa Mill.) and oak (Quercus petraea) on the expression of glucose transporter genes and the uptake of glucose and HT constituents in a 3D porcine-small-intestine epithelial-cell model. The viability of epithelial cells CLAB and PSI exposed to different HTs was determined using alamarBlue®. qPCR was used to analyze the gene expression of SGLT1, GLUT2, GLUT4, and POLR2A. Glucose uptake was confirmed Citation: Brus, M.; Frangež, R.; by assay, and LC–MS/ MS was used for the analysis of HT bioavailability.
    [Show full text]
  • Interplay Between Metformin and Serotonin Transport in the Gastrointestinal Tract: a Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin
    INTERPLAY BETWEEN METFORMIN AND SEROTONIN TRANSPORT IN THE GASTROINTESTINAL TRACT: A NOVEL MECHANISM FOR THE INTESTINAL ABSORPTION AND ADVERSE EFFECTS OF METFORMIN Tianxiang Han A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Eshelman School of Pharmacy. Chapel Hill 2013 Approved By: Dhiren R. Thakker, Ph.D. Michael Jay, Ph.D. Kim L. R. Brouwer, Pharm.D., Ph.D. Joseph W. Polli, Ph.D. Xiao Xiao, Ph.D. © 2013 Tianxiang Han ALL RIGHTS RESERVED ii ABSTRACT TIANXIANG HAN: Interplay between Metformin and Serotonin Transport in the Gastrointestinal Tract: A Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin (Under the direction of Dhiren R. Thakker, Ph.D.) Metformin is a widely prescribed drug for Type II diabetes mellitus. Previous studies have shown that this highly hydrophilic and charged compound traverses predominantly paracellularly across the Caco-2 cell monolayer, a well-established model for human intestinal epithelium. However, oral bioavailability of metformin is significantly higher than that of the paracellular probe, mannitol (~60% vs ~16%). Based on these observations, the Thakker laboratory proposed a “sponge” hypothesis (Proctor et al., 2008) which states that the functional synergy between apical (AP) transporters and paracellular transport enhances the intestinal absorption of metformin. This dissertation work aims to identify AP uptake transporters of metformin, determine their polarized localization, and elucidate their roles in the intestinal absorption and adverse effects of metformin. Chemical inhibition and transporter-knockdown studies revealed that four transporters, namely, organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT), serotonin reuptake transporter (SERT) and choline high-affinity transporter (CHT) contribute to AP uptake of metformin in Caco-2 cells.
    [Show full text]
  • Distribution of Glucose Transporters in Renal Diseases Leszek Szablewski
    Szablewski Journal of Biomedical Science (2017) 24:64 DOI 10.1186/s12929-017-0371-7 REVIEW Open Access Distribution of glucose transporters in renal diseases Leszek Szablewski Abstract Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney. Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three families of glucose transporters: GLUT proteins, sodium-dependent glucose transporters (SGLTs) and SWEET. In kidney, only GLUTs and SGLTs protein are expressed. Mutations within genes that code these proteins lead to different renal disorders and diseases. However, diseases, not only renal, such as diabetes, may damage expression and function of renal glucose transporters. Keywords: Kidney, GLUT proteins, SGLT proteins, Diabetes, Familial renal glucosuria, Fanconi-Bickel syndrome, Renal cancers Background Because glucose is hydrophilic and soluble in water, lipid Maintenance of glucose homeostasis prevents pathological bilayer of plasma membrane is impermeable for it. There- consequences due to prolonged hyperglycemia or fore, transport of glucose into cells depends on carrier pro- hypoglycemia. Hyperglycemia leads to a high risk of vascu- teins that are present in the plasma membrane. In humans, lar complications, nephropathy, neuropathy and retinop- there are three families of glucose transporters: GLUT pro- athy. Hypoglycemia may damage the central nervous teins, encoded by SLC2 genes; sodium-dependent glucose system and lead to a higher risk of death.
    [Show full text]
  • Supplementary Material Dynamic Modulation of Glucose Utilisation By
    Supplementary Material Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease 1 Model Development Glucose uptake by cells depends on a familiy of glucose transport membrane proteins, GLUTs, with GLUT1- 4 isoforms posessing well-known roles as glucose transporters in different cell types [Thorens and Mueckler, 2009; Mueckler and Thorens, 2013]. The total glucose uptake per unit of time can be estimated as the sum of the average whole-body glucose uptake mediated by GLUT1-4. However, different cell types present different distributions of GLUTs in their cell membranes, with each GLUT possessing a different affinity for extracellular glucose. This is often represented via their associated Michaelis-Menten constant Km [Joost and Thorens, 2001; Unger, 1991]. The differential affinity poises cells to respond selectively to different plasma glucose concentrations, from normal physiological dynamic ranges (e.g., fasting and feeding) to pathological (e.g., diabetes and other metabolic disorders). In general, GLUT1 and GLUT3 transporters can be regarded as high affinity transporters (low Km) that provide basic glucose supply to most cells, whereas GLUT4 contribute differentially to glucose uptake in muscle cells and adypocytes through a process dependent on insulin, glucocorticoids, and other factors. Conversely, GLUT2 transporters have a lower affinity for glucose (high Km) and are highly expressed in β cells and liver, where they are regarded as glucose sensors that mediate insulin secretion by β cells and trigger glycogenolysis in the liver [Unger, 1991; Scheepers et al., 2004]. In adypocytes and muscle cells, GLUT1, GLUT3 and GLUT4 amplify glucose uptake via an insulin- dependent mechanism that translocates these transporters from intracellular pools to the cell membrane [Scheepers et al., 2004; Wilson et al., 1995].
    [Show full text]
  • Colocalization of GLUT2 Glucose Transporter, Sodium/Glucose
    Rapid Publications Colocalization of GLUT2 Glucose Transporter, Sodium/Glucose Cotransporter, and 7-Glutamyl Transpeptidase in Rat Kidney With Double-Peroxidase Immunocytochemistry STEVEN C. CRAMER, WILLIAM M. PARDRIDGE, BRUCE A. HIRAYAMA, AND ERNEST M. WRIGHT Glucose is reabsorbed from the glomerular filtrate in unreactive to the GLUT2 antiserum suggests that the proximal segment of the renal tubule in two stages. either the SGLT1 epitope is conserved on a related The first stage is uphill transport across the brush brush border protein or that there is another GLUT border membrane by Na+-glucose cotransport and the transporter responsible for the exit of sugar from these second stage is downhill transport across the proximal tubule cells. Diabetes 41:766-70, 1992 basolateral membrane by facilitated diffusion. Genes for both a renal Na+-glucose cotransporter (SGLT1) and a renal facilitated glucose transporter (GLUT2) have been cloned and sequenced. To examine whether lucose is >90% reabsorbed at the proximal SGLT1 and GLUT2 colocalize to the same tubular epithelial cells in rat kidney, double-immunoperoxidase tubule of the kidney (1,2). Physiological stud- studies with dual chromogens and paraformaldehyde ies supported the model of glucose transport perfusion-fixed frozen sections of rat kidney were through two membranes in series, i.e., the Gbrush border and basolateral membranes of the kidney performed. Antipeptide antisera were prepared against rat GLUT2 (amino acids 510-522) and rabbit SGLT1 tubule epithelium via the concerted action of a Na+- (amino acids 402-420). Proximal tubules were glucose transporter and a Na+-independent glucose identified immunocytochemically with an antiserum transporter, respectively (3,4).
    [Show full text]
  • The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’S Not All Bad
    nutrients Review The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad Emily S. Krueger 1 , Trevor S. Lloyd 1,2 and Jeffery S. Tessem 1,* 1 Department of Nutrition, Dietetics and Food Science, Brigham Young University, Provo, UT 84602, USA; [email protected] (E.S.K.); [email protected] (T.S.L.) 2 Medical Education Program, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA * Correspondence: [email protected]; Tel.: +1-801-422-9082 Abstract: Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic β-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial Citation: Krueger, E.S.; Lloyd, T.S.; molecular effects observed in metabolic disease research.
    [Show full text]
  • Transporters
    Alexander, S. P. H., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP Collaborators (2019). The Concise Guide to Pharmacology 2019/20: Transporters. British Journal of Pharmacology, 176(S1), S397-S493. https://doi.org/10.1111/bph.14753 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1111/bph.14753 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wiley at https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14753. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Transporters. British Journal of Pharmacology (2019) 176, S397–S493 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters Stephen PH Alexander1 , Eamonn Kelly2, Alistair Mathie3 ,JohnAPeters4 , Emma L Veale3 , Jane F Armstrong5 , Elena Faccenda5 ,SimonDHarding5 ,AdamJPawson5 , Joanna L Sharman5 , Christopher Southan5 , Jamie A Davies5 and CGTP Collaborators 1School of Life Sciences,
    [Show full text]
  • WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic B-Cells
    Diabetes Volume 68, February 2019 377 WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic b-Cells Li Ding, Lingling Han, John Dube, and Daniel D. Billadeau Diabetes 2019;68:377–386 | https://doi.org/10.2337/db18-0189 WASH is an endosomal protein belonging to the Wiskott- family 2 (SLC2A) genes (8). Glut2 is well established as the Aldrich syndrome protein superfamily that participates in principal membrane Glut with low affinity in rodent endosomal receptor trafficking by facilitating tubule fis- pancreatic b-cells (9,10), and previous studies using sion via activation of the ubiquitously expressed Arp2/3 a transgenic mouse model showed that Glut2-null mice complex. While several studies have begun to elucidate generated by homologous recombination provoked severe an understanding of the functions of WASH in cells lines, glycosuria and died at around the weaning period with the in vivo function of WASH has not been fully eluci- a diabetic phenotype (11). Importantly, pancreatic-specific dated, since total body deletion in mice leads to early expression of Glut2 in Glut2-null mice restored normal embryonic lethality. To circumvent this problem, we have glucose-stimulated insulin secretion (GSIS) and glucose- PATHOPHYSIOLOGY used a WASH conditional knockout mouse model to stimulated insulin biosynthesis (12). In addition, Glut2 investigate the role of WASH in the pancreas. We find protein levels in pancreatic islets are strongly reduced that pancreas-specific deletion of WASH leads to im- with loss of GSIS in numerous animal models of diabe- paired blood glucose clearance and reduced insulin re- tes (13–17). Although the mechanism for Glut2 protein lease upon glucose stimulation.
    [Show full text]
  • 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.
    [Show full text]
  • Cross-Talk Between Insulin and Serotonin
    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.
    [Show full text]
  • Glucose Transporters As a Target for Anticancer Therapy
    cancers Review Glucose Transporters as a Target for Anticancer Therapy Monika Pliszka and Leszek Szablewski * Chair and Department of General Biology and Parasitology, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-22-621-26-07 Simple Summary: For mammalian cells, glucose is a major source of energy. In the presence of oxygen, a complete breakdown of glucose generates 36 molecules of ATP from one molecule of glucose. Hypoxia is a hallmark of cancer; therefore, cancer cells prefer the process of glycolysis, which generates only two molecules of ATP from one molecule of glucose, and cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by cancer cells is due to increased expression of glucose transporters. However, overexpression of glucose transporters, promoting the process of carcinogenesis, and increasing aggressiveness and invasiveness of tumors, may have also a beneficial effect. For example, upregulation of glucose transporters is used in diagnostic techniques such as FDG-PET. Therapeutic inhibition of glucose transporters may be a method of treatment of cancer patients. On the other hand, upregulation of glucose transporters, which are used in radioiodine therapy, can help patients with cancers. Abstract: Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP.
    [Show full text]
  • Serotonin Regulates Glucose-Stimulated Insulin Secretion from Pancreatic Β Cells During Pregnancy
    Serotonin regulates glucose-stimulated insulin secretion from pancreatic β cells during pregnancy Mica Ohara-Imaizumia,1, Hail Kimb,c,1, Masashi Yoshidad, Tomonori Fujiwarae, Kyota Aoyagia, Yukiko Toyofukuf, Yoko Nakamichia, Chiyono Nishiwakia, Tadashi Okamurag, Toyoyoshi Uchidaf, Yoshio Fujitanif, Kimio Akagawae, Masafumi Kakeid, Hirotaka Watadaf, Michael S. Germanc,h,2, and Shinya Nagamatsua,2 Departments of aBiochemistry and eCell Physiology Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; bGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; cDiabetes Center and Hormone Research Institute and hDepartment of Medicine, University of California, San Francisco, CA 94143; dFirst Department of Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Saitama 337-8503, Japan; fDepartment of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; and gSection of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan Edited* by William J. Rutter, Synergenics, LLC, Burlingame, CA, and approved October 18, 2013 (received for review June 13, 2013) In preparation for the metabolic demands of pregnancy, β cells in Htr3b encode subunits of the serotonin-gated cation channel Htr3 the maternal pancreatic islets increase both in number and in glu- (19, 20). Five identical Htr3a subunits or a mixture of Htr3a and cose-stimulated insulin secretion (GSIS) per cell. Mechanisms have Htr3b make up a functional Htr3 channel (21). The channel is pre- + + been proposed for the increased β cell mass, but not for the in- dominantly Na -andK -selective, and its opening in response to creased GSIS.
    [Show full text]