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Corinna Schölch

Untersuchungen des Leptin-Systems und des Stoffwechsels juveniler Ratten: Zwei Adipositas-Modelle


Endogenous as well as chemical functional teratogens, if administered in critical periods of neuronal development, may destroy central regulatory mechanisms and therefore lead to lifelong-lasting dysfunctions of endocrine regulatory loops. In this study acute changes in energy balance during suckling period has been examined in two rat obesity models, which are known to induce an obese phenotype in the adult animal.

In the first obesity model a postnatal overnutrition (PNO) has been induced by rearing pups in small litters of only 4 animals (small litter size) compared to pups reared under control conditions with 12 pups (normal litter size). Besides Wistar rats either Zucker rats, which are heterozygous for a leptin receptor defect „fatty“ (+/fa), or wildtyp Zucker rats have been used in this study. All PNO-animal showed an enhanced fat-free dry-mass (FFDM) as well as an increased body-fat mass compared to their control littermates, which had been reared in litters of normal size. The enlarged fat deposition of heterozygous animals which is normally hardly detectable by phenotype is massively enhanced by the postnatal overnutrition. Besides the increase in body fat mass the +/fa-PNO as well as the PNO-Wistar rats developed a relative hyperleptinaemia. This was associated with a leptin resistance, which was expressed in a nearly total insensitivity exspecially of the PNO-Wistar- and PNO-+/fa-Zucker rats against peripheral leptin treatment. The investigation of hypothalamic leptin receptor binding in Zucker rats revealed that neither PNO- nor leptin-treated animals had a different binding compared to the controll animals. Independent of these findings, a diminished leptin receptor binding of heterozygous and female animals could be detected.

These results of the first obesity model show that a higher energy supply in postnatal life not only contributes to a higher body weight but exspecially supports an exaggerated fat deposition. Additionally, this study demonstrated an obvious interaction between an usually inconspicous genetic trait and early postnatal enviromental influences, which could be exemplary for the programming of phenotypical expression of genetic disorders. Independant of genetic background, a leptin resistance as a lead-symptom develops, which is not caused by an altered expression of the leptin receptor.

In the second obesity model monosodiumglutamate (MSG) in high doses has been used to lesion neuronal cell bodies in specific hypothalamic areas without a blood-brain-barrier. Postnatal MSG-treatment causes a diminshed fat-deposition of the treated suckling-age animals compared to the control (NaCl-treated) animals. Artificial rearing which ensures asupply with identical amounts of milk via intraosophageal catheters revealed a nearly complete suppression of the circadian torpor-like decreases of Tc and MR in the daily minimum and therefore lead to a higher energy dissipation of the MSG-treated animals. The artificially reared animals showed also a diminished fat mass compared to the control animals in accordance with the observed changes in energy metabolism which thus were causal for the reduction of body weight. To study the effect of MSG treatment on hypothalamic nuclei, which are known to be involved in regulation of energy homeostasis, cresyl-violet stained brain sections have been examined. A marked loss of cells in the arcuate nucleus (ARC) could be detected while other brain regions were not affected by the treatment. Additionally, to test whether those brain regions are already functional at an age of ten days, the expression of the Fos protein, an immediate early-gene-product, which is known as a marker for neuronal activity, could be demonstrated. Despite the neuronal immaturity of ten day old rat pups the NPY-ergic projections, which have been shown to be essential for signal transmission in the control of food intake, already exist.

The results show that MSG-induced obesity, which develops in adulthood, is preceded by a period of expanded energy expenditure in juvenile life. With respect to their effects on energy metabolism leptin treatment and MSG lesioning of juvenile pups are comparable and lead mainly to a diminished fat deposition. For the interpretation of these findings one has to keep in mind the histological results, which revealed that even at this early age the transmission of the leptin signal to the nucleus paraventricularis is already possible, because the NPY-ergic connectivities are already existent. The neuronal cell death in the ARC leads to an leptin-like disinhibition of normal energy saving mechanisms in the minimum of the daily circadian rhythm in 10 day old pups.

Summarizing the results, this study shows that two totally different influences - postnatal overnutrition or a chemical teratogene - if administered in periods that are critical for developing organisms, can induce changes in energy metabolism and nutritional state of animals which may lead to a higher obesity susceptibility in adulthood.

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