Entwicklung der Adipositas und Neuropeptidexpression bei Melanokortin-4-Rezeptor-defizienten Mäusen unter besonderer Berücksichtigung der Haltungsbedingungen

Der Melanokortin-4-Rezeptor-Defekt (mit einer Prävalenz von 2-6% in einem adipösen Patientenkollektiv) ist die bisher am häufigsten nachgewiesene monogenetische Form der Adipositas beim Menschen. Daher ist es auch in Bezug auf die Relevanz beim Menschen interessant, ein Mausmodell mit einem MC4-Reze...

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Bibliographic Details
Main Author: Weide, Karin
Contributors: Schmidt, Ingrid (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2006
Online Access:PDF Full Text
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Until now the deficiency of the melanocortin-4-receptor (MC4R) is the most frequently diagnosed monogenic cause for obesity in humans. 2-6% of extremely obese patients display relevant mutations in the MC4-receptor. MC4R-deficient mice are a suitable animal model to explore the genetic and environmental impacts on development of obesity. It is used in the present study to analyse onset and development of obesity from early after birth and at defined ages during development to adulthood. With standard laboratory ambient temperature and feeding conditions as control, the study has also tried to account for the human living conditions in industrialised countries by maintaining animals at thermoneutral ambient temperature with supplementary access to a high caloric food. The mRNA expressions of NPY, AGRP, POMC and CART were analysed in the arcuate nucleus of 35-day-old mice under standard conditions and in animals with supplementary high caloric food living at thermoneutral ambient temperature. Data obtained by determining body mass, body composition, plasma leptin, food intake, oxygen consumption, and neuropeptide expression levels were subjected to statistical analysis with the aim to obtain insights into the development of obesity and associated changes in central control of energy balance in MC4R-deficient mice. Beginning at the age of 35 days differences in body mass and body fat content become detectable in mice under standard conditions, depending on sex and genotype. At this age animals show a significant difference between +/+ and -/- animals. On day 56 there is also a significant difference between +/+ and +/- animals. From 35 days of age onward males exhibit a higher FFDM than females. The comparison of body composition of mice under standard conditions with mice having access to high caloric food and thermoneutral ambient temperature reveals a significant influence of housing conditions, sex and genotype on body mass, body fat and body fat content. These influences are similar in 56-day-old animals in which there is also an influence of genotype on FFDM, but no influence of housing conditions on body mass and no influence of sex on body fat. Compared with mice under standard conditions, animals with supplementary high caloric food living at thermoneutral ambient temperature show a decrease of FFDM and an increase of body fat content. Under these conditions wild-types, heterozygous and homozygous mice increase their body fat content. 35-day-old wild-types doubled and 56 day-old +/+ females nearly quadrupled their body fat content. Under standard conditions plasma leptin of mice at the same age is correlated with body fat and body fat content independently of sex and genotype. 85% of the variability of plasma leptin depends on body fat content and only 1% on genotype. High caloric food and thermoneutral ambient temperature result in significantly higher plasma leptin levels in females than in males. Statistical analysis of cumulative food intake from weaning until day 35 or 56 shows for 35-day-old animals a significant influence of litter, sex and genotype and a genotype/sex interaction. The results of 56-day-old mice resemble those for the younger animals, but no genotype/sex interaction is found. At both ages females show a higher preference for high caloric food than males. The measurement of oxygen consumption reveals higher oxygen consumption for -/- mice than for wild-types and heterozygous mice. Hyperphagia not hypometabolism causes obesity in MC4R-deficient mice. The animals increase their metabolic rate less than in proportion to their increase in food intake. The study shows significant negative correlations between the expression of the orexigenic neuropeptides NPY and AGRP and body fat content, but does not show significant correlations for the anorexigenic neuropeptides POMC and CART. For all four neuropeptides analysis of covariance verified a significantly lower expression of mRNA for animals with access to high caloric food and thermoneutral ambient temperature. Under these conditions melanocortin-4-receptor deficiency causes an earlier break-down of counter-regulation against obesity than under standard conditions.