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

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Dpp4RatB-1a B cell differentiation  IMP  RGD 
Dpp4Ratpositive regulation of natural killer cell mediated immunity  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DA.F344-Dpp4DPPIV/SvHRatdecreased anxiety-related response  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased anxiety-related response  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased anxiety-related response  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased circulating adrenocorticotropin level  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased circulating adrenocorticotropin level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased circulating adrenocorticotropin level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased circulating alanine transaminase level  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased circulating alanine transaminase level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased circulating alanine transaminase level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased circulating alkaline phosphatase level  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased circulating alkaline phosphatase level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased circulating alkaline phosphatase level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased circulating aspartate transaminase level  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased circulating aspartate transaminase level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased circulating aspartate transaminase level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased circulating corticosterone level  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased circulating corticosterone level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased circulating corticosterone level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased circulating interleukin-6 level  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased circulating interleukin-6 level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased circulating interleukin-6 level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased circulating triglyceride level  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased circulating triglyceride level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased circulating triglyceride level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased eosinophil cell number  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased eosinophil cell number  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased eosinophil cell number  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased interleukin-6 secretion  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased interleukin-6 secretion  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased interleukin-6 secretion  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased lymphocyte cell number  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased lymphocyte cell number  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased lymphocyte cell number  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased response to stress-induced hyperthermia  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased response to stress-induced hyperthermia  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased response to stress-induced hyperthermia  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased susceptibility to diet-induced obesity inducedIAGPcontrolled calorie content dietcompared to DA/ZtmRGD 
Dpp4Ratdecreased susceptibility to diet-induced obesity  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased susceptibility to diet-induced obesity  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatdecreased susceptibility to weight gain  IAGP compared to DA/ZtmRGD 
Dpp4Ratdecreased susceptibility to weight gain  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatdecreased susceptibility to weight gain  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatimpaired natural killer cell mediated cytotoxicity  IAGP compared to DA/ZtmRGD 
Dpp4Ratimpaired natural killer cell mediated cytotoxicity  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatimpaired natural killer cell mediated cytotoxicity  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatimproved glucose tolerance inducedIAGPglucose solutioncompared to DA/ZtmRGD 
Dpp4Ratimproved glucose tolerance  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatimproved glucose tolerance  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatincreased B-1 B cell number  IAGP compared to DA/ZtmRGD 
Dpp4Ratincreased B-1 B cell number  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatincreased B-1 B cell number  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatincreased blood urea nitrogen level  IAGP compared to DA/ZtmRGD 
Dpp4Ratincreased blood urea nitrogen level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatincreased blood urea nitrogen level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatincreased circulating glucagon level  IAGP compared to DA/ZtmRGD 
Dpp4Ratincreased circulating glucagon level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatincreased circulating glucagon level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatincreased circulating phosphate level  IAGP compared to DA/ZtmRGD 
Dpp4Ratincreased circulating phosphate level  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatincreased circulating phosphate level  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatincreased exploration in new environment  IAGP compared to DA/ZtmRGD 
Dpp4Ratincreased exploration in new environment  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatincreased exploration in new environment  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatincreased NK cell number  IAGP compared to DA/ZtmRGD 
Dpp4Ratincreased NK cell number  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatincreased NK cell number  IAGP compared to DA/ZtmRGD 
DA.F344-Dpp4DPPIV/SvHRatweight loss inducedIAGPcontrolled gliadin content dietcompared to DA/ZtmRGD 
Dpp4Ratweight loss  IAGP compared to DA/ZtmRGD 
Dpp4DPPIVRatweight loss  IAGP compared to DA/ZtmRGD 
Objects Annotated

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

Strains
DA.F344-Dpp4DPPIV/SvH  (NA)


Additional Information