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1000 Titel
  • Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver
1000 Autor/in
  1. Hinrichs, Arne |
  2. Kessler, Barbara |
  3. Kurome, Mayuko |
  4. Blutke, Andreas |
  5. Kemter, Elisabeth |
  6. Bernau, Maren |
  7. Scholz, Armin M. |
  8. Rathkolb, Birgit |
  9. Renner, Simone |
  10. Bultmann, Sebastian |
  11. Leonhardt, Heinrich |
  12. de Angelis, Martin Hrabĕ |
  13. Nagashima, Hiroshi |
  14. Hoeflich, Andreas |
  15. Blum, Werner F. |
  16. Bidlingmaier, Martin |
  17. Wanke, Rüdiger |
  18. Dahlhoff, Maik |
  19. Wolf, Eckhard |
1000 Erscheinungsjahr 2018
1000 LeibnizOpen
1000 Art der Datei
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2018-03-15
1000 Erschienen in
1000 Quellenangabe
  • 11: 113-128
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2018
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1016/j.molmet.2018.03.006 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001387/ |
1000 Ergänzendes Material
  • https://www.sciencedirect.com/science/article/pii/S2212877818302114?via%3Dihub#appsec2 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • OBJECTIVE: Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized. METHODS: CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue. RESULTS: GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation of JAK2 was significantly increased, possibly due to the increased serum leptin levels and increased hepatic leptin receptor expression and activation in GHR-KO pigs. In addition, increased mTOR phosphorylation was observed in GHR-KO liver samples, and phosphorylation studies of downstream substrates suggested the activation of mainly mTOR complex 2. CONCLUSION: GHR-KO pigs resemble the pathophysiology of LS and are an interesting model for mechanistic studies and treatment trials.
1000 Sacherschließung
lokal Dwarfism
lokal Signaling
lokal Growth hormone receptor
lokal Laron syndrome
lokal Pig model
lokal Hypoglycemia
lokal Insulin-like growth factor 1
1000 Fachgruppe
  1. Medizin |
  2. Biologie |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/SGlucmljaHMsIEFybmU=|https://frl.publisso.de/adhoc/creator/S2Vzc2xlciwgQmFyYmFyYQ==|https://frl.publisso.de/adhoc/creator/S3Vyb21lLCBNYXl1a28=|https://frl.publisso.de/adhoc/creator/Qmx1dGtlLCBBbmRyZWFz|https://frl.publisso.de/adhoc/creator/S2VtdGVyLCBFbGlzYWJldGg=|https://frl.publisso.de/adhoc/creator/QmVybmF1LCBNYXJlbg==|https://frl.publisso.de/adhoc/creator/U2Nob2x6LCBBcm1pbiBNLg==|https://frl.publisso.de/adhoc/creator/UmF0aGtvbGIsIEJpcmdpdA==|https://frl.publisso.de/adhoc/creator/UmVubmVyLCBTaW1vbmU=|https://frl.publisso.de/adhoc/creator/QnVsdG1hbm4sIFNlYmFzdGlhbg==|https://frl.publisso.de/adhoc/creator/TGVvbmhhcmR0LCBIZWlucmljaA==|https://frl.publisso.de/adhoc/creator/ZGUgQW5nZWxpcywgTWFydGluIEhyYWLElQ==|https://frl.publisso.de/adhoc/creator/TmFnYXNoaW1hLCBIaXJvc2hp|http://orcid.org/0000-0003-2018-2836|https://frl.publisso.de/adhoc/creator/Qmx1bSwgV2VybmVyIEYu|https://frl.publisso.de/adhoc/creator/QmlkbGluZ21haWVyLCBNYXJ0aW4=|https://frl.publisso.de/adhoc/creator/V2Fua2UsIFLDvGRpZ2Vy|https://frl.publisso.de/adhoc/creator/RGFobGhvZmYsIE1haWs=|https://frl.publisso.de/adhoc/creator/V29sZiwgRWNraGFyZA==
1000 Label
1000 Förderer
  1. German Center for Diabetes Research (DZD) |
  2. German Research Foundation (DFG) |
1000 Fördernummer
  1. -
  2. TRR127
1000 Förderprogramm
  1. -
  2. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer German Center for Diabetes Research (DZD) |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer German Research Foundation (DFG) |
    1000 Förderprogramm -
    1000 Fördernummer TRR127
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6410824.rdf
1000 Erstellt am 2018-10-26T12:38:59.844+0200
1000 Erstellt von 122
1000 beschreibt frl:6410824
1000 Bearbeitet von 218
1000 Zuletzt bearbeitet Thu Jan 30 19:20:58 CET 2020
1000 Objekt bearb. Tue Dec 18 12:36:58 CET 2018
1000 Vgl. frl:6410824
1000 Oai Id
  1. oai:frl.publisso.de:frl:6410824 |
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