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.

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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.

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Gene Ontology Annotations

Biological Process

B-1a B cell differentiation (IMP)

positive regulation of natural killer cell mediated immunity (IMP)

Phenotype Annotations

Mammalian Phenotype

decreased anxiety-related response (IAGP)

decreased circulating adrenocorticotropin level (IAGP)

decreased circulating alanine transaminase level (IAGP)

decreased circulating alkaline phosphatase level (IAGP)

decreased circulating aspartate transaminase level (IAGP)

decreased circulating corticosterone level (IAGP)

decreased circulating interleukin-6 level (IAGP)

decreased circulating triglyceride level (IAGP)

decreased eosinophil cell number (IAGP)

decreased interleukin-6 secretion (IAGP)

decreased lymphocyte cell number (IAGP)

decreased response to stress-induced hyperthermia (IAGP)

decreased susceptibility to diet-induced obesity (IAGP)

decreased susceptibility to weight gain (IAGP)

impaired natural killer cell mediated cytotoxicity (IAGP)

improved glucose tolerance (IAGP)

increased B-1 B cell number (IAGP)

increased blood urea nitrogen level (IAGP)

increased circulating glucagon level (IAGP)

increased circulating phosphate level (IAGP)

increased exploration in new environment (IAGP)

increased NK cell number (IAGP)

weight loss (IAGP)

Objects Annotated

Genes (Rattus norvegicus)

Dpp4 (dipeptidylpeptidase 4)

Dpp4^DPPIV (dipeptidylpeptidase 4; DPPIV mutant)

Strains

DA.F344-Dpp4^DPPIV/SvH (NA)

Additional Information

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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.

Mammalian Phenotype