Browsing by Subject "Fettsucht"

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    Die Regulation der Futteraufnahme beim Schwein - Untersuchung der Wirkungen eines Serotonin Noradrenalin Wiederaufnahmehemmers (Sibutramin) und eines MCH-R1 Antagonisten (Compound B4)
    (2007) Sommer, Torsten; Claus, Rolf
    The regulation of food- and feed intake is a highly topical investigative area in animal husbandry as well as in human medicine. Here the focus of medicine is primarily on the reduction of food intake and at the same time change of the metabolism to increased energy expenditure in order to counteract the rising number of adiposity and metabolic syndrome. Therefore, substances from pharmacological research are known which act in different nuclei of the hypothalamus and control food intake and energy expenditure. In the present study two of these new substances were examined with regards to their impact on pigs. The results lead to a more detailed understanding of the corresponding mechanisms in pigs, one of the most important animals used in agriculture. In addition, the pig is also a suitable model for human pharmacological research, as it equals the human physiological regulation more than the rat, which is the most common animal model. Study work flow: Two different regulative substances were examined, on the one hand a serotonin noradrenalin reuptake inhibitor (Sibutramine) and on the other hand, a melanin concentrating hormone receptor antagonist (MCH-R1 antagonist; Compound B4). For the evaluation of the effectiveness the following factors were measured; feed intake, water consumption, weight gain, feed conversion rate and the development of body fat content. The changes caused in the regulation of the metabolism were evaluated by anabolic (Growth hormone and IGF-I) and catabolic (cortisol and aldosterone) hormones. In addition, thyroid hormones and urea in the blood plasma were measured as a parameter of protein turnover. The study was divided in three trials, each of them taking six weeks. During the first trial sibutramine was given per os to three animals and three animals were kept as control. During the second trial sibutramine was given intravenously to two animals and two animals were kept as control. During the third trial the MCH-R1 antagonist, Compound B4, was given per os to six animals. The results are described in the following sections. Results of the sibutramine application: The pharmacological effectiveness of sibutramine is mainly explained through its metabolites (desmethyl sibutramine and didesmethyl sibutramine). It was found that for the per os intake of 20 mg/kg LW sibutramine, as well as sibutramine as the first metabolite desmethyl-sibutramine, a lower concentration in the blood plasma existed compared to the intravenous application. Whereas concentration of the second metabolite didesmethyl-sibutramine was higher for per os application than for intravenous application. Since the effectiveness of sibutramine is mainly based on its second metabolite didesmethyl-sibutramine, the way of application was crucial for its effectiveness. This means that the intravenous application was ineffective. After per os application feed intake was significantly reduced, also dependent on the dose applied, but did not lead to a reduced weight gain of the animals. Further, no impact was found on the feed conversion ratio. In contrast, the treatment with sibutramine per os led to significantly increased water consumption. The application of sibutramine had no impact on the growth hormone secretion. However, IGF-1 concentration was increased while feed intake was decreased. The cortisol concentration in blood plasma was not impacted by any treatment. Results of the application of the MCH-R1 antagonist (Compound B4): The application of the antagonist led to a significant reduction of feed intake, dependent on the dose applied. The means derived for daily weight gain show considerable individual differences per animal, hence the reduction of daily weight gain overall was not significant. Further, changes in water consumption were also detected in this trial. However, it could not be clarified if this was caused by the application of the antagonist or the reduced feed intake. Generally, the application of Compound B4 tends to result in energy saving mechanisms, which have an impact on metabolic active hormones. IGF-1 for example, was slightly lower in the control phase. Neither sibutramine nor the MCH-R1 antagonist Compound B4 had any impact on the concentration of thyroid hormones or cortisol. Conclusions: The studies have shown that the MCH-R1 antagonist leads to a significant reduction of feed intake in pigs, whereas the metabolic active hormones, and therefore the energy expenditure, do not seem to be impacted at all. In addition, it was proven that the pig is a useful animal model for such human pharmacological investigations. However, the large amount of substances required can be seen as disadvantageous and as a limiting factor in the investigation of new agents with an initially small amount of substance synthesis.
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    The role of NLRC5 in obesity
    (2024) Bauer, Sarah Katharina; Kufer, Thomas
    Obesity and its associated morbidities are major global health problems. It has become evident in the last decades that the state of obesity is intimately linked with our immune system. Pattern recognition receptors (PRRs), the main sensor molecules of the innate immune system, were shown to play an essential role in the pathology of obesity and its associated morbidities. Among others, members of the nucleotide-binding and oligomerization domain (NOD) -like receptors (NLRs), a family of cytosolic PRRs, were associated with the obesity-accompanying low-grade inflammatory response contributing to obesity-associated morbidities. NLRC5 is a NLR protein functioning as key transcriptional regulator of major histocompatibility complex (MHC) class I genes responsible for antigen presentation. Recent observations now suggest novel roles of NLRC5 in metabolic trades, but so far, no confirmation of these singular observations is available, and the underlying mechanisms remain elusive. The aim of this thesis was to characterize the role of the NLR protein NLRC5 in obesity. To this end, two Nlrc5 deficient mouse lines (Nlrc5 deltaExon4-7 and Nlrc5 deltaExon4) were subjected to high-fat diet (HFD) feeding and phenotypic, morphological, and biochemical analyses were performed. Female Nlrc5 deltaExon4-7 mice presented with higher body and adipose tissue (AT) weight gain and larger adipocytes compared to wildtype (WT) animals. This phenotype, however, could not be recapitulated in the Nlrc5 deltaExon4 mouse line. Microbiome analysis revealed subtle alterations of the faecal microbiome by diet:genotype interactions. To further characterize the effect of NLRC5 deficiency on adipocyte differentiation, the CRISPR/Cas9 gene editing system was used to modify Nlrc5 expression in the 3T3-L1 preadipocyte cell line. Using inducible HeLa cell lines with stable GFP-NLRC5 expression we showed NLRC5 to interact with the master regulator of adipogenesis peroxisome proliferator-activated receptor y (PPARy) and to enhance the expression of PPARy target genes. In addition, a contribution of NLRC5 to PPARy’s anti-inflammatory actions was revealed using NLRC5 deficient THP-1 macrophage-like cells and bone marrow-derived macrophages from Nlrc5 deltaExon4-7 mice. To elucidate the mechanism behind the synergy between NLRC5 and PPARy, reporter gene and chromatin immunoprecipitation (ChIP) assays were performed. Lastly, the expression of multiple NLR family members was correlated with body mass index (BMI) in obese human patients and investigated in the adipose tissue and liver of HFD-fed mice, the latter revealing Nlrp10 to be highly upregulated by HFD feeding. Taken together, this thesis provides a comprehensive characterization of Nlrc5 deficient mice on HFD and reveals a function of NLRC5 as transcriptional co-regulator of PPARy targets and its anti-inflammatory properties. In addition, this work provides first insights into the potential mechanism behind the synergistic transcriptional regulation by NLRC5 and PPARy and extends the knowledge on the regulation of NLR expression by HFD feeding.