DOCSLIB.ORG

Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice Dana K. Sindelar,1 Paul Mystkowski,1 Donald J. Marsh,2 Richard D. Palmiter,2 and Michael W. Schwartz1 The combined effects of increased hypothalamic signal- these responses when the stimulus is food deprivation. ing by neuropeptide Y (NPY) and decreased signaling by Moreover, fasting is a more potent stimulus to hypotha- melanocortins are hypothesized to stimulate food in- lamic AgRP gene expression than is STZ-diabetes. take when body fat stores are depleted. To investigate Therefore, central nervous system melanocortin signal- NPY’s role in the hyperphagic response to uncontrolled ing appears to be suppressed more effectively by fasting diabetes, streptozotocin (STZ) (200 mg/kg intraperito- than by uncontrolled diabetes, which provides a plausi- neally) or saline vehicle was given to NPY-deficient ble explanation for differences in the feeding response :Npy–/–) and wild-type (Npy؉/؉) mice. In Npy؉/؉ mice, to these two stimuli in mice lacking NPY. Diabetes 51) STZ-induced diabetes increased mean daily food intake 778–783, 2002 to plateau values 50% above baseline intake (؉2.0 ؎ 0.6 g/day; P < 0.05), an effect that was not seen in STZ- treated Npy–/– mice (؉0.8 ؎ 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and com- daptive increases of food intake induced by parably decreased levels of body weight, fat content, depleted body energy stores are important for and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy–/– mice exhibit intact survival and appear to involve the coordinate hyperphagic responses to fasting (Erickson et al. [1], A regulation of multiple hypothalamic pathways Nature 381:415–418, 1996). To investigate whether dif- that can influence feeding behavior (2). For example, ferences in hypothalamic melanocortin signaling can hypothalamic neurons that contain neuropeptide Y (NPY), explain this discrepancy, we used in situ hybridization a potent stimulator of food intake, are activated when to compare the effects of STZ-diabetes and fasting on body fat content is reduced by energy restriction (3). pro-opiomelanocortin (POMC) and agouti-related pep- Conversely, the hypothalamic production of melanocort- tide (AgRP) mRNA levels in the hypothalamic arcuate ؉ ؉ ins (peptides with anorexic properties that are cleaved nucleus (ARC) of Npy–/– and Npy / mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, from pro-opiomelanocortin [POMC]) is reduced in this but the increase in STZ-diabetes was small (50–80%) setting (4). Acute or chonic energy deficits also increase compared with the effect of fasting (ϳ20-fold increase expression of the gene encoding agouti-related peptide of AgRP mRNA). STZ-diabetes also lowered POMC (AgRP), an endogenous antagonist of central nervous -mRNA levels by 65% in the ARC of Npy؉/؉ mice (P < system (CNS) melanocortin receptors (5) that is co-ex –/– 0.05) but by only 11% in Npy mice (NS); fasting pressed with NPY in neurons of the hypothalamic arcuate significantly lowered POMC mRNA levels in both geno- nucleus (ARC) (6). Fasting is an especially potent stimulus types. We conclude that NPY is required for both the to AgRP gene expression in mouse ARC, increasing AgRP increase of food intake and the decrease of hypotha- ϳ lamic POMC gene expression induced by uncontrolled mRNA by 20-fold (6). The combined effects of decreased diabetes. In contrast, NPY is not required for either of melanocortin signaling (due to both increased AgRP and decreased POMC biosynthesis) and increased NPY signal- ing, therefore, comprise an integrated mechanism to me- From the 1Department of Medicine, University of Washington, and Howard diate hyperphagia in response to a sustained energy Hughes Medical Institute, University of Washington, Seattle, Washington; and the 2Department of Biochemistry, University of Washington, Seattle, Wash- deficit. ington. The original description of mice with NPY deficiency Address correspondence and reprint requests to Michael W. Schwartz, –/– Harborview Medical Center, Division of Endocrinology, Box 359757, 325 9th (Npy ) due to targeted NPY gene disruption revealed Ave., Seattle, WA 98104. E-mail: [email protected]. them to have normal levels of daily food intake and body Received for publication 20 June 2001 and accepted in revised form 3 weight and to exhibit normal increases of food intake after December 2001. M.W.S. is on the Scientific Advisory Board of Millennium Pharmaceutical a fast (1). One possible explanation for this finding is that and has received consulting fees for work in this capacity. D.K.S. is currently neural control over feeding under these circumstances is employed as Senior Investigator at Eli Lilly, Inc., a position that he accepted sufficiently redundant that the loss of NPY is compensated after his work on this study was completed. D.J.M. is currently employed as Senior Investigator at Merck Pharmaceuticals, Inc., a position that he ac- for by other responses. Of potential importance in this cepted after his work on this study was completed. context is the marked reduction of melanocortin signaling Current address for D.K.S.: Eli Lilly & Co., Corporate Center, Drop 0545, –/– Indianapolis, IN 46285. Current address for D.J.M.: Merck & Co., Inc., induced by fasting, which may allow Npy mice to RY80T-126, P.O. Box 2000, Rahway, NJ 07065. increase food intake appropriately during refeeding. One AgRP, agouti-related peptide; ARC, hypothalamic arcuate nucleus; AUC, approach to test this hypothesis is to identify and study a area under the curve; CNS, central nervous system; Mcr, melanocortin receptor; MRS, magnetic resonance spectroscopy; NPY, neuropeptide Y; model in which hyperphagia depends more on increased POMC, pro-opiomelanocortin; STZ, streptozotocin. NPY signaling than on reduced melanocortin signaling. In 778 DIABETES, VOL. 51, MARCH 2002 D.K. SINDELAR AND ASSOCIATES such a model, the ability to increase food intake should be the same assay. Hybridization to NPY, POMC, or AgRP mRNA was performed 33 compromised in NPY-deficient mice. with antisense riboprobes transcribed from cDNA templates using [ P]UTP (5,16). The hybridization signal in the arcuate nucleus of each brain slice was Uncontrolled insulin-deficient diabetes induced by the determined from film autoradiograms using the MCID image analysis system ␤-cell toxin streptozotocin (STZ) is an established model (Imaging Research, St. Catherines, ON, Canada) as previously described (16). of sustained hyperphagia in rodents. Like the response to Both the film density and hybridization image area were measured, and the fasting, diabetic hyperphagia appears to involve increased product of these two measures was calculated as an index of mRNA content. Values for each animal reflect the mean of 6–12 measurements per animal. hypothalamic signaling by NPY (7–10) and is also accom- The mean value of each neuropeptide mRNA level obtained for wild-type panied by increased AgRP mRNA and reduced POMC controls (e.g., vehicle-treated Npyϩ/ϩ mice for the STZ-diabetes study or mRNA expression in ARC neurons (11–13). However, the Npyϩ/ϩ mice fed ad libitum for the fasting study) was considered to represent increase of AgRP mRNA levels induced by STZ-induced 100% of the control value for that study, and all individual hybridization values diabetes in mice appears to be much smaller (ϳ2-fold) from each experiment were normalized to this number. ϳ Body composition. Body fat content was determined post mortem in mice (13) than that induced by fasting ( 20-fold) (5). Diabetic from experiment 1 using magnetic resonance spectroscopy (MRS) as previ- hyperphagia may therefore depend to a greater extent on ously reported (17). Mice were placed within a custom-made radiofrequency NPY than on AgRP when compared to the hyperphagic coil used for both transmitting and receiving the resonant proton signal at response to fasting. 200.1 MHz. Body lipid mass was estimated from the area under the curve (AUC) of the lipid peak of the resultant MRS spectra, as previously described Based on this reasoning, we hypothesized that mice (17). For each genotype, the mean AUC for the lipid peak in the nondiabetic lacking NPY would manifest impaired feeding responses group was considered to represent 100% of the control value of relative body to uncontrolled diabetes, despite intact responses to fast- fat content, and individual AUC values for the diabetic groups were expressed ing (which induces a much larger increase of AgRP as a percent of this value. expression). Evidence that the orexigenic response to Plasma assays. Blood samples were collected on heparin and placed ϩ/ϩ immediately on ice in heparinized tubes. Plasma was separated by centrifu- centrally administered AgRP is heightened in Npy mice gation and stored at Ϫ20°C until determination of glucose and leptin concen- (14) provides additional support for this hypothesis. We trations. Plasma glucose was determined by the glucose oxidase method therefore measured food intake and hypothalamic levels (Beckman Instruments, Brea, CA). Plasma leptin levels were determined by of AgRP and POMC mRNA in Npy–/– and Npyϩ/ϩ mice radioimmunoassay (Linco Research, St. Louis, MO). Statistics. All values are reported as group means Ϯ SE. The level of made diabetic with STZ and compared these responses to significance was taken as P Յ 0.05, two-tailed. Data were analyzed for those induced by a 48-h fast in separate groups of each differences from baseline values using one-way ANOVA with repeated mea- genotype. sures, and Fisher’s protected least significance difference test was used for multiple comparisons when significant F ratios were obtained. Interactions between treatment and genotype were analyzed by group mean comparisons RESEARCH DESIGN AND METHODS using two-way ANOVA. Statistical comparisons were made using Statview Animals. Adult mice (C57Bl/6x129Sv/Ev mixed genetic background or pure (Calabasa, CA) software. 129Sv/Ev background) with targeted knockout of the Npy gene (Npy–/–) and wild-type littermate controls (Npyϩ/ϩ) were housed in individual cages in standard vivarium conditions (12 h:12 h light:dark cycle).
Load more

Recommended publications
  • One-Month of High-Intensity Exercise Did Not Change the Food Intake And
    This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/ by-nc-nd/3.0), which permits copy and redistribute the material in any medium or format, provided the original work is properly cited. 8 ENDOCRINE REGULATIONS, Vol. 53, No. 1, 8–13, 2019 doi:10.2478/enr-2019-0002 One-month of high-intensity exercise did not change the food intake and the hypothalamic arcuate nucleus proopiomelanocortin and neuropeptide Y expression levels in male Wistar rats Nazli Khajehnasiri1, Homayoun Khazali2, Farzam Sheikhzadeh3, Mahnaz Ghowsi4 1Department of Biological Sciences, Faculty of Basic Sciences, Higher Education Institute of Rab-Rashid, Tabriz, Iran; 2Department of Animal Sciences and Biotechnology, Faculty of Biological Sciences and Technology, Shahid Beheshti University, Tehran, Iran; 3Department of Animal Sciences, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; 4Department of Biology, Faculty of Sciences, Razi University, Kermanshah, Iran E-mail: [email protected] Objective. The hypothalamic arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) circuitries are involved in the inhibition and stimulation of the appetite, respectively. The aim of this study was to investigate the effects of one-month lasting high-intensity exercise on the POMC mRNA and NPY mRNA expression in the above-mentioned brain structure and appetite and food intake levels. Methods. Fourteen male Wistar rats (250±50 g) were used and kept in the well-controlled con- ditions (22±2 °C, 50±5% humidity, and 12 h dark/light cycle) with food and water ad libitum. The rats were divided into two groups (n=7): 1) control group (C, these rats served as controls) and 2) exercised group (RIE, these rats performed a high-intensity exercise for one month (5 days per week) 40 min daily with speed 35 m/min.
    [Show full text]
  • Dietary Fat Alters the Response of Hypothalamic Neuropeptide Y to Subsequent Energy Intake in Broiler Chickens Xiao J
    © 2017. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2017) 220, 607-614 doi:10.1242/jeb.143792 RESEARCH ARTICLE Dietary fat alters the response of hypothalamic neuropeptide Y to subsequent energy intake in broiler chickens Xiao J. Wang, Shao H. Xu, Lei Liu, Zhi G. Song, Hong C. Jiao and Hai Lin* ABSTRACT Several studies have shown that these hypothalamic neuropeptides Dietary fat affects appetite and appetite-related peptides in birds and are sensitive to body energy status and critical to whole-body mammals; however, the effect of dietary fat on appetite is still unclear metabolic adjustment. NPY reduces energy expenditure by in chickens faced with different energy statuses. Two experiments decreasing adipose tissue thermogenesis (Egawa et al., 1991; Patel were conducted to investigate the effects of dietary fat on food intake et al., 2006; Chao et al., 2011; Zhang et al., 2014). The obesity of and hypothalamic neuropeptides in chickens subjected to two ob/ob mice is attenuated when NPY is knocked out (Erickson et al., fi feeding states or two diets. In Experiment 1, chickens were fed a 1996; Segal-Lieberman et al., 2003). NPY de ciency attenuates high-fat (HF) or low-fat (LF) diet for 35 days, and then subjected to fed responses to a palatable high fat diet in mice (Hollopeter et al., 1998; (HF-fed, LF-fed) or fasted (HF-fasted, LF-fasted) conditions for 24 h. Patel et al., 2006). Animals in which POMC neurons have been In Experiment 2, chickens that were fed a HF or LF diet for 35 days knocked out are obese and hyperphagic (Butler and Cone, 2002; were fasted for 24 h and then re-fed with HF (HF-RHF, LF-RHF) or LF Mencarelli et al., 2012; Diané et al., 2014; Raffan et al., 2016).
    [Show full text]
  • Neuropeptide Y in the Amygdala Induces Long-Term
    The Journal of Neuroscience, January 23, 2008 • 28(4):893–903 • 893 Behavioral/Systems/Cognitive Neuropeptide Y in the Amygdala Induces Long-Term Resilience to Stress-Induced Reductions in Social Responses But Not Hypothalamic–Adrenal–Pituitary Axis Activity or Hyperthermia Tammy J. Sajdyk,1 Philip L. Johnson,1 Randy J. Leitermann,3 Stephanie D. Fitz,1 Amy Dietrich,1 Michelle Morin,2 Donald R. Gehlert,2 Janice H. Urban,3 and Anantha Shekhar1 1Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202, 2Eli Lilly, Indianapolis, Indiana 46201, and 3Department of Physiology and Biophysics and Interdepartmental Neurosciences Program, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064 Resilience to mental and physical stress is a key determinant for the survival and functioning of mammals. Although the importance of stress resilience has been recognized, the underlying neural mediators have not yet been identified. Neuropeptide Y (NPY) is a peptide known for its anti-anxiety-like effects mediated via the amygdala. The results of our current study demonstrate, for the first time that repeated administration of NPY directly into the basolateral nucleus of the amygdala (BLA) produces selective stress-resilient behavioral responses to an acute restraint challenge as measured in the social interaction test, but has no effect on hypothalamic–adrenal–pituitary axisactivityorstress-inducedhyperthermia.Moreimportantly,theresilientbehaviorsobservedintheNPY-treatedanimalswerepresent for up to 8 weeks. Antagonizing the activity of calcineurin, a protein phosphatase involved in neuronal remodeling and present in NPY receptor containing neurons within the BLA, blocked the development of long-term, but not the acute increases in social interaction responses induced by NPY administration.
    [Show full text]
  • Neuropeptides Controlling Energy Balance: Orexins and Neuromedins
    Neuropeptides Controlling Energy Balance: Orexins and Neuromedins Joshua P. Nixon, Catherine M. Kotz, Colleen M. Novak, Charles J. Billington, and Jennifer A. Teske Contents 1 Brain Orexins and Energy Balance ....................................................... 79 1.1 Orexin............................................................................... 79 2 Orexin and Feeding ....................................................................... 80 3 Orexin and Arousal ....................................................................... 83 J.P. Nixon • J.A. Teske Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA C.M. Kotz (*) Veterans Affairs Medical Center, GRECC (11 G), Minneapolis, MN, USA Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA e-mail: [email protected] C.M. Novak Department of Biological Sciences, Kent State University, Kent, OH, USA C.J. Billington Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Veterans Affairs Medical Center, Endocrine Unit (111 G), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA H.-G. Joost (ed.), Appetite Control, Handbook of Experimental Pharmacology 209, 77 DOI 10.1007/978-3-642-24716-3_4, # Springer-Verlag Berlin Heidelberg 2012 78 J.P. Nixon et al. 4 Orexin Actions on Endocrine and Autonomic Systems ................................. 84 5 Orexin, Physical Activity, and Energy Expenditure ....................................
    [Show full text]
  • Evolution of the Neuropeptide Y and Opioid Systems and Their Genomic
    It's time to try Defying gravity I think I'll try Defying gravity And you can't pull me down Wicked List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Sundström G, Larsson TA, Brenner S, Venkatesh B, Larham- mar D. (2008) Evolution of the neuropeptide Y family: new genes by chromosome duplications in early vertebrates and in teleost fishes. General and Comparative Endocrinology Feb 1;155(3):705-16. II Sundström G, Larsson TA, Xu B, Heldin J, Lundell I, Lar- hammar D. (2010) Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a and Y8b. Manuscript III Sundström G, Xu B, Larsson TA, Heldin J, Bergqvist CA, Fredriksson R, Conlon JM, Lundell I, Denver RJ, Larhammar D. (2010) Characterization of the neuropeptide Y system's three peptides and six receptors in the frog Silurana tropicalis. Manu- script IV Dreborg S, Sundström G, Larsson TA, Larhammar D. (2008) Evolution of vertebrate opioid receptors. Proc Natl Acad Sci USA Oct 7;105(40):15487-92. V Sundström G, Dreborg S, Larhammar D. (2010) Concomitant duplications of opioid peptide and receptor genes before the origin of jawed vertebrates. PLoS One May 6;5(5):e10512. VI Sundström G, Larsson TA, Larhammar D. (2008) Phylogenet- ic and chromosomal analyses of multiple gene families syntenic with vertebrate Hox clusters. BMC Evolutionary Biology Sep 19;8:254. VII Widmark J, Sundström G, Ocampo Daza D, Larhammar D. (2010) Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes.
    [Show full text]
  • Rfamide Peptides: Structure, Function, Mechanisms and Pharmaceutical Potential
    Pharmaceuticals 2011, 4, 1248-1280; doi:10.3390/ph4091248 OPEN ACCESS Pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review RFamide Peptides: Structure, Function, Mechanisms and Pharmaceutical Potential Maria Findeisen †, Daniel Rathmann † and Annette G. Beck-Sickinger * Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany; E-Mails: [email protected] (M.F.); [email protected] (D.R.) † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +49-341-9736900; Fax: +49-341-9736909. Received: 29 August 2011; in revised form: 9 September 2011 / Accepted: 15 September 2011 / Published: 21 September 2011 Abstract: Different neuropeptides, all containing a common carboxy-terminal RFamide sequence, have been characterized as ligands of the RFamide peptide receptor family. Currently, five subgroups have been characterized with respect to their N-terminal sequence and hence cover a wide pattern of biological functions, like important neuroendocrine, behavioral, sensory and automatic functions. The RFamide peptide receptor family represents a multiligand/multireceptor system, as many ligands are recognized by several GPCR subtypes within one family. Multireceptor systems are often susceptible to cross-reactions, as their numerous ligands are frequently closely related. In this review we focus on recent results in the field of structure-activity studies as well as mutational exploration of crucial positions within this GPCR system. The review summarizes the reported peptide analogs and recently developed small molecule ligands (agonists and antagonists) to highlight the current understanding of the pharmacophoric elements, required for affinity and activity at the receptor family.
    [Show full text]
  • Calcitonin Gene-Related Peptide and Other Peptides
    P1: KWW/KKL P2: KWW/HCN QC: KWW/FLX T1: KWW GRBT050-16 Olesen- 2057G GRBT050-Olesen-v6.cls July 9, 2005 4:30 ••Chapter 16 ◗ Calcitonin Gene-Related Peptide and Other Peptides Susan Brain and Lars Edvinsson Vasoactive peptides can be either stored or synthesized de THE CGRP FAMILY OF PEPTIDES novo before release from a range of tissues in the brain or from the walls of intracranial vasculature. In this chapter, The expression of mRNA from the calcitonin gene is tissue we concentrate on neuropeptides that are released from specific in that CGRP mRNA is predominantly expressed perivascular nerves. These include calcitonin gene-related in nerves and calcitonin mRNA in the thyroid (5). The 37 peptide (CGRP), substance P, neurokinin A, nociceptin, amino acid peptide CGRP belongs to a family that include somatostatin, and opioids (Table 16-1). The endothelium the more recently discovered peptides adrenomedullin produces the potent vasoconstrictors endothelin and an- that is primarily produced by non-neuronal tissues, espe- giotensin, and dilators such as nitric oxide, prostacyclin, cially vascular tissues and amylin that is mainly produced and endothelium-derived hyperpolarizing factors. In ad- in the pancreas. They share some structural homology (ap- dition there are circulating agents; among these the most proximately 25–40%) and also some, but not total, similar- potent is 5-hydroxytryptamine. The neuronal messengers ities in biological activities (see Brain and Grant [11] for stored in the intracranial vessels have been reviewed recent review). CGRP is abundant in the body and has a (32) and it was revealed that sympathetic nerves store wide distribution throughout the central and peripheral noradrenaline, neuropeptide Y, and ATP, the parasympa- nervous systems.
    [Show full text]
  • Co-Regulation of Hormone Receptors, Neuropeptides, and Steroidogenic Enzymes 2 Across the Vertebrate Social Behavior Network 3 4 Brent M
    bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Co-regulation of hormone receptors, neuropeptides, and steroidogenic enzymes 2 across the vertebrate social behavior network 3 4 Brent M. Horton1, T. Brandt Ryder2, Ignacio T. Moore3, Christopher N. 5 Balakrishnan4,* 6 1Millersville University, Department of Biology 7 2Smithsonian Conservation Biology Institute, Migratory Bird Center 8 3Virginia Tech, Department of Biological Sciences 9 4East Carolina University, Department of Biology 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Running Title: Gene expression in the social behavior network 2 Keywords: dominance, systems biology, songbird, territoriality, genome 3 Corresponding Author: 4 Christopher Balakrishnan 5 East Carolina University 6 Department of Biology 7 Howell Science Complex 8 Greenville, NC, USA 27858 9 [email protected] 10 2 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Stress Susceptibility-Specific Phenotype Associated with Different
    Lisowski et al. BMC Neuroscience 2013, 14:144 http://www.biomedcentral.com/1471-2202/14/144 RESEARCH ARTICLE Open Access Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice Pawel Lisowski1*, Grzegorz R Juszczak2, Joanna Goscik3, Adrian M Stankiewicz2, Marek Wieczorek4, Lech Zwierzchowski1 and Artur H Swiergiel5,6 Abstract Background: The effects of chronic treatment with tricyclic antidepressant (desipramine, DMI) on the hippocampal transcriptome in mice displaying high and low swim stress-induced analgesia (HA and LA lines) were studied. These mice displayed different depression-like behavioral responses to DMI: stress-sensitive HA animals responded to DMI, while LA animals did not. Results: To investigate the effects of DMI treatment on gene expression profiling, whole-genome Illumina Expres- sion BeadChip arrays and qPCR were used. Total RNA isolated from hippocampi was used. Expression profiling was then performed and data were analyzed bioinformatically to assess the influence of stress susceptibility-specific phe- notypes on hippocampal transcriptomic responses to chronic DMI. DMI treatment affected the expression of 71 genes in HA mice and 41 genes in LA mice. We observed the upregulation of Igf2 and the genes involved in neuro- genesis (HA: Sema3f, Ntng1, Gbx2, Efna5, and Rora; LA: Otx2, Rarb, and Drd1a) in both mouse lines. In HA mice, we observed the upregulation of genes involved in neurotransmitter transport, the termination of GABA and glycine ac- tivity (Slc6a11, Slc6a9), glutamate uptake (Slc17a6), and the downregulation of neuropeptide Y (Npy) and cortico- tropin releasing hormone-binding protein (Crhbp). In LA mice, we also observed the upregulation of other genes involved in neuroprotection (Ttr, Igfbp2, Prlr) and the downregulation of genes involved in calcium signaling and ion binding (Adcy1, Cckbr, Myl4, Slu7, Scrp1, Zfp330).
    [Show full text]
  • Calcitonin Gene-Related Peptide: Understanding Its Role S
    Educational Forum Calcitonin gene-related peptide: Understanding its role S. Ghatta, D. Nimmagadda ABSTRACT Department of Calcitonin gene-related peptide (CGRP), a 37 amino acid neuropeptide, identified in multiple spe- Pharmaceutical cies, has widespread distribution and expression. CGRP acts through G protein-coupled receptors Sciences, College of whose presence and changes in function modulate the peptide’s effects in various tissues. Three Pharmacy, North Dakota State University, receptor subtypes have been identified and CGRP‘s signal transduction through the receptors is Fargo ND 58105, USA. dependent on two accessory proteins: Receptor activity modifying protein1 (RAMP1) and Receptor component protein (RCP). Several endogenous substances such as glucocorticoids, nitric oxide Received: 15.4.2004 (NO), nerve growth factors (NGF), and steroid hormones modulate CGRP release and synthesis. Revised: 24.5.2004 Both peptide and non-peptide agonists and antagonists of CGRP receptors are being developed. Accepted: 20.6.2004 Also the therapeutic benefits of some antagonists such as BIBN 4096 BS in migraine have been Correspondence to: promising. This brief review provides a preliminary understanding of the diverse biological effects Srinivas Ghatta of the peptide in various systems. The current status of CGRP and its receptors in many pathophysi- E-mail: ological states is not fully explored and future findings are greatly awaited. [email protected] KEY WORDS: Calcitonin-receptor like receptor, CGRP receptor, cAMP, signal transduction Introduction sory neurons of spinal cord. There are two isoforms available: αCGRP and βCGRP1 which are derived from different genes. Calcitonin gene-related peptide (CGRP), identified in 1982, βCGRP differs from αCGRP by three amino acids in rats and belongs to the calcitonin family of neuropeptides which also by one in humans.
    [Show full text]
  • Neuropeptide Y and Peptide YY in Association with Depressive
    nutrients Article Neuropeptide Y and Peptide YY in Association with Depressive Symptoms and Eating Behaviours in Adolescents across the Weight Spectrum: From Anorexia Nervosa to Obesity Marta Tyszkiewicz-Nwafor 1,* , Katarzyna Jowik 1, Agata Dutkiewicz 1, Agata Krasinska 2 , Natalia Pytlinska 1, Monika Dmitrzak-Weglarz 3, Marta Suminska 2 , Agata Pruciak 4, Bogda Skowronska 2,† and Agnieszka Slopien 1,† 1 Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland; [email protected] (K.J.); [email protected] (A.D.); [email protected] (N.P.); [email protected] (A.S.) 2 Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, 61-701 Poznan, Poland; [email protected] (A.K.); [email protected] (M.S.); [email protected] (B.S.) 3 Psychiatric Genetics Unit, Department of Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland; [email protected] 4 Institute of Plant Protection—National Research Institute, Research Centre of Quarantine, Invasive and Genetically Modified Organisms, 60-318 Poznan, Poland; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Citation: Tyszkiewicz-Nwafor, M.; Jowik, K.; Dutkiewicz, A.; Krasinska, Abstract: Neuropeptide Y (NPY) and peptide YY (PYY) are involved in metabolic regulation. The A.; Pytlinska, N.; Dmitrzak-Weglarz, purpose of the study was to assess the serum levels of NPY and PYY in adolescents with anorexia M.; Suminska, M.; Pruciak, A.; nervosa (AN) or obesity (OB), as well as in a healthy control group (CG). The effects of potential Skowronska, B.; Slopien, A. confounders on their concentrations were also analysed.
    [Show full text]
  • Growing up POMC: Pro-Opiomelanocortin in the Developing Brain
    Growing Up POMC: Pro-opiomelanocortin in the Developing Brain Stephanie Louise Padilla Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2011 © 2011 Stephanie Louise Padilla All Rights Reserved ABSTRACT Growing Up POMC: Pro-opiomelanocortin in the Developing Brain Stephanie Louise Padilla Neurons in the arcuate nucleus of the hypothalamus (ARH) play a central role in the regulation of body weight and energy homeostasis. ARH neurons directly sense nutrient and hormonal signals of energy availability from the periphery and relay this information to secondary nuclei targets, where signals of energy status are integrated to regulate behaviors related to food intake and energy expenditure. Transduction of signals related to energy status by Pro-opiomelanocortin (POMC) and neuropeptide-Y/agouti-related protein (NPY/AgRP) neurons in the ARH exert opposing influences on secondary neurons in central circuits regulating energy balance. My thesis research focused on the developmental events regulating the differentiation and specification of cell fates in the ARH. My first project was designed to characterize the ontogeny of Pomc- and Npy-expressing neurons in the developing mediobasal hypothalamus (Chapter 2). These experiments led to the unexpected finding that during mid-gestation, Pomc is broadly expressed in the majority of newly-born ARH neurons, but is subsequently down-regulated during later stages of development as cells acquire a terminal cell identity. Moreover, these studies demonstrated that most immature Pomc-expressing progenitors subsequently differentiate into non-POMC neurons, including a subset of functionally distinct NPY/AgRP neurons.
    [Show full text]