Skip to main content
SpringerLink
Log in

Expression of neuropeptide Y and agouti-related peptide in the hypothalamic arcuate nucleus of newborn neurogenin3 null mutant mice

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Mice deficient in neurogenin 3 (Ngn3) fail to generate pancreatic endocrine cells and intestinal endocrine cells. Hypothalamic neuropeptides implicated in the control of energy homeostasis might also be affected in Ngn3 homozygous null mutant mice. We investigated the expression of two prominent orexigenic neuropeptides, neuropeptide Y (NPY) and agouti-related protein (AgRP), in the hypothalamic arcuate nucleus of newborn wild-type and Ngn3 null mutant mice. Immunohistochemical analysis demonstrated that, in Ngn3 null mutants, the number of NPY-immunoreactive neurons and nerve fibers was markedly increased in the arcuate nucleus, and the nerve fibers were widely distributed in the hypothalamic area, including the paraventricular and dorsomedial nuclei. Little increase of AgRP immunoreactivity was detected in the arcuate nucleus of mutant mice. In situ hybridization analysis confirmed the increased population of the NPY neurons in the arcuate nucleus of the mutants. The NPY mRNA level, as estimated by laser capture microdissection and real-time quantitative polymerase chain reaction, was 371% higher in Ngn3 null mutants than in wild-type mice. AgRP mRNA levels did not differ significantly between the null mutants and wild-type mice. Thus, up-regulation of the hypothalamic NPY system is probably a feature characteristic of Ngn3 null mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Badman MK, Flier JS (2005) The gut and energy balance: visceral allies in the obesity wars. Science 307:1909–1914

    Article  CAS  PubMed  Google Scholar 

  • Beck B (2006) Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos Trans R Soc Lond Biol 361:1159–1185

    Article  CAS  PubMed  Google Scholar 

  • Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ, Woods SC (2002) The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 22:9048–9052

    CAS  PubMed  Google Scholar 

  • Bouret SG, Draper SJ, Simerly RB (2004) Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 24:2797–2805

    Article  CAS  PubMed  Google Scholar 

  • Broberger C, Johansen J, Johansson C, Schalling M, Hökfelt T (1998) The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci USA 95:15043–15048

    Article  CAS  PubMed  Google Scholar 

  • Broberger C, Johansen J, Brismar H, Johansson C, Schalling M, Hökfelt T (1999) Changes in neuropeptide Y receptors and pro-opiomelanocortin in the anorexia (anx/anx) mouse hypothalamus. J Neurosci 19:7130–7139

    CAS  PubMed  Google Scholar 

  • Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller-Wieland D, Kahn CR (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289:2122–2125

    Article  PubMed  Google Scholar 

  • Cordido F, Isidro ML, Nemina R, Sangiao-Alvarellos S (2009) Ghrelin and growth hormone secretagogues, physiological and pharmacological aspect. Curr Drug Discov Technol 6:334–342

    Article  Google Scholar 

  • Elias CFG, Saper CB, Marotos-Flier E, Tritos NA, Lee C, Kelly J, Tatro JB, Hoffman GE, Olimann MM, Barsh GS, Sakurai T, Yanagisawa M, Elmquist JK (1998) Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 402:442–459

    Article  CAS  PubMed  Google Scholar 

  • Gardiner JV, Jayasena CN, Bloom SR (2008) Gut hormones: a weight off your mind. J Neuroendocrinol 20:834–841

    Article  CAS  PubMed  Google Scholar 

  • Gradwohl G, Dierich A, LeMeur M, Guillemot F (2000) Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 97:1607–1611

    Article  CAS  PubMed  Google Scholar 

  • Grove KL, Smith MS (2003) Ontogeny of the hypothalamic neuropeptide Y system. Physiol Behav 79:47–63

    Article  CAS  PubMed  Google Scholar 

  • Grove KL, Allen S, Grayson BE, Smith MS (2003) Postnatal development of the hypothalamic neuropeptide Y system. Neuroscience 116:393–406

    Article  CAS  PubMed  Google Scholar 

  • Hahn TM, Breininger JF, Baskin DG, Schwartz MW (1998) Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 4:271–272

    Google Scholar 

  • Havel PJ, Hahn TM, Sindelar DK, Baskin DG, Dallman MF, Weigle DS, Schwartz MW (2000) Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortic system and muscle uncoupling protein 3 expression in rats. Diabetes 49:244–252

    Article  CAS  PubMed  Google Scholar 

  • Hidaka S, Yoshimatsu H, Kondou S, Oka K, Tsuruta Y, Sakino H, Itateyama E, Noguchi H, Himeno K, Okamoto K, Teshima Y, Okeda T, Sakata T (2001) Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in sterptozotocin-induced diabetic rats. J Neurochem 77:993–1000

    Article  CAS  PubMed  Google Scholar 

  • Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141

    Article  CAS  PubMed  Google Scholar 

  • Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M, Gradwohl G (2002) Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J 21:6338–6347

    Article  CAS  PubMed  Google Scholar 

  • Kagotani Y, Hashimoto T, Tsuruo Y, Kawano H, Daikoku S, Chihara K (1989) Development of the neuronal system containing neuropeptide Y in the rat hypothalamus. Int J Dev Neurosci 7:359–374

    Article  CAS  PubMed  Google Scholar 

  • Kameda Y, Miura M, Ohno S (1998) Localization and development of chromogranin A and luteinizing hormone immunoreactivities in the secretory-specific cells of the hypophyseal pars tuberalis of the chicken. Histochem Cell Biol 109:211–222

    Article  CAS  PubMed  Google Scholar 

  • Kameda Y, Miura M, Nishimaki T (2001) Localization of neuropeptide Y mRNA and peptide in the chicken hypothalamus and their alterations after food deprivation, dehydration, and castration. J Comp Neurol 436:376–388

    Article  CAS  PubMed  Google Scholar 

  • Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I (2001) Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and agouti-related protein mRNA levels and body weight in rats. Diabetes 50:2438–2443

    Article  CAS  PubMed  Google Scholar 

  • Luquet S, Perez FA, Hnasko TS, Palmiter RD (2005) NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310:683–685

    Article  CAS  PubMed  Google Scholar 

  • Moran TH, Dailey MJ (2009) Gut peptides: targets for antiobesity drug development. Endocrinology 150:2526–2530

    Article  CAS  PubMed  Google Scholar 

  • Murphy KG, Dhillo WS, Bloom SR (2006) Gut peptides in the regulation of food intake and energy homeostasis. Endocr Rev 27:719–727

    Article  CAS  PubMed  Google Scholar 

  • Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001) A role for ghrelin in the central regulation of feeding. Nature 409:192–198

    Article  Google Scholar 

  • Obici S (2009) Molecular targets for obesity therapy in the brain. Endocrinology 150:2512–2517

    Article  CAS  PubMed  Google Scholar 

  • Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278:135–138

    Article  CAS  PubMed  Google Scholar 

  • Sahu A, Kalra PS, Kalra SP (1988) Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus. Peptides 9:83–86

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG (1997) Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuatae nucleus. Diabetes 46:2119–2123

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671

    CAS  PubMed  Google Scholar 

  • Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL (1997) Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 11:593–602

    Article  CAS  PubMed  Google Scholar 

  • Sipols AJ, Baskin DG, Schwartz MW (1995) Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 44:147–151

    Article  CAS  PubMed  Google Scholar 

  • Stanley BG, Leibowitz SF (1985) Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA 82:3940–3943

    Article  CAS  PubMed  Google Scholar 

  • Willesen MG, Kristensen P, Rømer J (1999) Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70:306–316

    Article  CAS  PubMed  Google Scholar 

  • Wilson BD, Bagnol D, Kaelin CB, Ollmann MM, Gantz I, Watson SJ, Barsh GS (1999) Physiological and anatomical circuitry between agouti-related protein and leptin signaling. Endocrinology 140:2387–2397

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy, Kitasato University School of Medicine, Kanagawa, 228-8555, Japan

    Yuta Arai & Yoko Kameda

  2. IGBMC, Inserm, U964, CRNS UMR 7104, University of Strasbourg, llkirch, France

    Gérard Gradwohl

Authors
  1. Yuta Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gérard Gradwohl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoko Kameda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoko Kameda.

Additional information

This work was supported in part by a Kitasato University Research Grant for Young Researchers to Y.A.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arai, Y., Gradwohl, G. & Kameda, Y. Expression of neuropeptide Y and agouti-related peptide in the hypothalamic arcuate nucleus of newborn neurogenin3 null mutant mice. Cell Tissue Res 340, 137–145 (2010). https://doi.org/10.1007/s00441-009-0925-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-009-0925-4

Keywords

Search

Navigation