Phänotypische und stoffwechselphysiologische Charakterisierung von ENU- (Ethylnitrosoharnstoff-) induzierten Mausmutanten mit gestörter Körpergewichtsregulation

Bei der ENU-Mutagenese und nachfolgenden phänotypischen Charakterisierung handelt es sich um einen am am Phänotyp orientierten, nicht Hypothesen-basierten Ansatz zur Gen-Funktionsanalyse (forward genetics). In dieser Arbeit erfolgte eine phänotypische und stoffwechselphysiologische Charakterisierung...

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Bibliographic Details
Main Author: Meyer, Carola
Contributors: Heldmaier, Gerhard (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2005
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Random mouse mutagenesis with a highly detailed phenotype-analysis is a successful forward genetics strategy for the detection and analysis of novel gene-function relationships. The present dissertation reports on the phenotypic and metabolic characteristics of two novel ENU (ethyl-nitroso-urea) induced mouse mutants exhibiting a dwarf phenotype: SMA1 and David. SMA1 carry an a to g missense mutation in exon 5 of the growth hormone (GH) gene, which translates to a D167G amino acid exchange in the mature protein. The phenotypic analyses indicate impaired storage and/or secretion of pituitary GH in mutants, resulting in reduced pituitary GH, and reduced GH stimulated IGF-1 (insulin-like growth factor 1) expression. The precise location of the David mutation, on the other hand, is presently unknown. Preliminary results on body composition in David mice suggested that body fat content (%) was lower in mutants, thus rendering David a putative mouse model for human anorexia. Using SMA1 as a model organism, a phenotypic and metabolic phenotyping program for ENU-derived phenotypes was established. Are SMA1-mice “just” smaller? In order to detect alterations in energy partitioning, metabolic rate, body temperature and assimilation efficiency were measured. The results indicate that SMA1 develop pronounced obesity, possibly supported by hyperghrelinemia, a decrease in body temperature, increased food intake and reduced daily energy expenditure. By metabolic characterisation, the anorectic phenotype of David could not be confirmed. In essence, the results show that body fat content and energy metabolism in David is proportionally reduced with body size.