RGD Reference Report - Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions. - Rat Genome Database

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Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions.

Authors: Frerker, Nadine  Raber, Kerstin  Bode, Felix  Skripuletz, Thomas  Nave, Heike  Klemann, Christian  Pabst, Reinhard  Stephan, Michael  Schade, Jutta  Brabant, Georg  Wedekind, Dirk  Jacobs, Roland  Jörns, Anne  Forssmann, Ulf  Straub, Rainer H  Johannes, Sigrid  Hoffmann, Torsten  Wagner, Leona  Demuth, Hans-Ulrich  von Hörsten, Stephan 
Citation: Frerker N, etal., Clin Chem Lab Med. 2009;47(3):275-87. doi: 10.1515/CCLM.2009.064.
RGD ID: 41408336
Pubmed: PMID:19327106   (View Abstract at PubMed)
DOI: DOI:10.1515/CCLM.2009.064   (Journal Full-text)


BACKGROUND: Treatment of diabetes type 2 using chronic pharmacological inhibition of dipeptidyl peptidase 4 (DP4) still requires an in-depth analysis of models for chronic DP4 deficiency, because adverse reactions induced by some DP4 inhibitors have been described.
METHODS: In the present study, a novel congenic rat model of DP4 deficiency on a "DP4-high" DA rat genetic background was generated (DA.F344-Dpp4(m)/ SvH rats) and comprehensively phenotyped.
RESULTS: Similar to chronic pharmacological inhibition of DP4, DP4 deficient rats exhibited a phenotype involving reduced diet-induced body weight gain and improved glucose tolerance associated with increased levels of glucagon-like peptide-1 (GLP-1) and bound leptin as well as decreased aminotransferases and triglycerides. Additionally, DA.F344-Dpp4(m)/SvH rats showed anxiolytic-like and reduced stress-like responses, a phenomenon presently not targeted by DP4 inhibitors. However, several immune alterations, such as differential leukocyte subset composition at baseline, blunted natural killer cell and T-cell functions, and altered cytokine levels were observed.
CONCLUSIONS: While this animal model confirms a critical role of DP4 in GLP-1-dependent glucose regulation, genetically induced chronic DP4 deficiency apparently also affects stress-regulatory and immuneregulatory systems, indicating that the use of chronic DP4 inhibitors might have the potential to interfere with central nervous system and immune functions in vivo.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
B-1a B cell differentiation  IMP 41408336 RGD 
positive regulation of natural killer cell mediated immunity  IMP 41408336 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased anxiety-related response  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased circulating adrenocorticotropin level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased circulating alanine transaminase level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased circulating alkaline phosphatase level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased circulating aspartate transaminase level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased circulating corticosterone level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased circulating interleukin-6 level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased circulating triglyceride level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased eosinophil cell number  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased interleukin-6 secretion  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased lymphocyte cell number  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased response to stress-induced hyperthermia  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
decreased susceptibility to diet-induced obesity inducedIAGPcontrolled calorie content diet41408336compared to DA/ZtmRGD 
decreased susceptibility to diet-induced obesity  IAGP 41408336; 41408336compared to DA/ZtmRGD 
decreased susceptibility to weight gain  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
impaired natural killer cell mediated cytotoxicity  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
improved glucose tolerance inducedIAGPglucose solution41408336compared to DA/ZtmRGD 
improved glucose tolerance  IAGP 41408336; 41408336compared to DA/ZtmRGD 
increased B-1 B cell number  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
increased blood urea nitrogen level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
increased circulating glucagon level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
increased circulating phosphate level  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
increased exploration in new environment  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
increased NK cell number  IAGP 41408336; 41408336; 41408336compared to DA/ZtmRGD 
weight loss inducedIAGPcontrolled gliadin content diet41408336compared to DA/ZtmRGD 
weight loss  IAGP 41408336; 41408336compared to DA/ZtmRGD 
Objects Annotated

Genes (Rattus norvegicus)
Dpp4  (dipeptidylpeptidase 4)
Dpp4DPPIV  (dipeptidylpeptidase 4; DPPIV mutant)

Strains
DA.F344-Dpp4DPPIV/SvH  (NA)


Additional Information