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Induction of lipid catabolism and mitochondrial biogenesis in white adipose tissue as therapeutic target for obesity and associated metabolic disorders
Adamcová, Kateřina ; Janovská, Petra (advisor) ; Tencerová, Michaela (referee) ; Cahová, Monika (referee)
Adipose tissue is not only crucial in the storage of excessive fat and its release but also plays important role in the secretion of endo/para- and autocrine factors, thus influencing energy metabolism on the whole body level. The incapability of adipose tissue to meet its responsibilities leads to whole-body metabolic problems resulting in type 2 diabetes, storing of fat in the liver, coronary disease, and other diseases. How to prevent development of obesity and its consequences and/or completely reverse it, is a subject of great scientific interest. Activation of brown adipose tissue (BAT) and brite cells via induction of uncoupling protein 1 (UCP1) and/or stimulation of UCP1-independent energy-dissipating metabolic pathways such as futile cycles in white adipose tissue may be a promising path to fulfill this goal. This thesis is based on results from experiments with two cold-exposed inbred murine strains differing in the propensity to obesity and murine experiments with diet-induced obesity prevented by n-3 polyunsaturated fatty acids (PUFA). Mice resistant to diet-induced obesity (A/J mice) showed higher induction of triacylglycerol (TAG)/fatty acid (FA) futile cycle in epididymal white adipose tissue by cold exposure in comparison to obesity-prone B6 mice. Interestingly, the level of both...
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The modification of gut microbiota composition by dietary intervention: the effect of plant-based and western-type diet
Ďásková, Nikola ; Cahová, Monika (advisor) ; Beneš, Jiří (referee) ; Tlaskalová - Hogenová, Helena (referee)
This thesis explores the relationship between diet, gut microbiota, and metabolic health, with a particular focus on their association with non-communicable metabolic diseases (NCDs) such as obesity and type 2 diabetes (T2D). The aim of the first study is to assess compositional and metabolic differences in gut microbiota between healthy lean long-term vegans and omnivores. The study reveals that while the gut microbiota composition is not significantly different between the two groups, there are significant differences in the fecal, serum and urinary metabolome. These differences may be attributed to the different availability of substrates in the diet, as the vegan diet is associated with a shift from a proteolytic to a saccharolytic fermentation program. Our results support the hypothesis of both resilience and metabolic flexibility of the adult gut microbiota. In addition to taxonomic analyses, this dissertation also includes metabolomics to evaluate the functional manifestations of the gut microbiota. We introduce a novel method to assess the ability of the gut microbiota to produce beneficial metabolites with a specific focus on butyrate synthesis using qPCR quantification of bacterial butyryl-CoA:acetate CoA-transferase. In silico, we identified bacteria among the human gut microbiota that...
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Regulation of VLDL production in the liver
Jirátová, Markéta ; Kovář, Jan (advisor) ; Cahová, Monika (referee)
The aim of this thesis is to summarize current knowledge about VLDL (very low density lipoprotein) assembly. In the first part of this thesis basic characteristics of lipids and lipoproteins are described. Lipids are the most favourable source of energy for animals. Lipoproteins are the macromolecular complexes that transport hydrofobic lipids in plasma. According to their density, they are classified to five groups: chylomicrons, VLDL, IDL, LDL, HDL. Second part of this thesis is focused on the apolipoproteins - structural peptide components of lipoproteins. The characteristics and functions of major apolipoprotein classes are explained with the main focus on apolipoproteins B that have an important role in VLDL assembly. The process of VLDL assembly is described in detail in the third part of the thesis. VLDL assembly consists of two steps. Pre-VLDL and lipid droplet are synthetized independently in the first step, for which apolipoprotein B-100 and microsomal triglyceride transfer protein (MTP) are essential. Second step is the fusion of pre-VLDL with the lipid droplet. ADP-ribosylation factor 1 (ARF1) and phospholipase D (PLD) are the essential components in the second step. Also apolipoprotein E, apolipoprotein A-V and acyl-coenzym A:cholesterol acyl transferasa 2 (ACAT2) are important. VLDL...
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Analysis of the involvement of α2 - AMPK in the beneficial effects of n-3 polyunsaturated fatty acids on obesity - associated metabolic derangements
Jeleník, Tomáš ; Rossmeisl, Martin (advisor) ; Cahová, Monika (referee) ; Pácha, Jiří (referee)
It is well established that n-3 polyunsaturated fatty acids with long chain (n-3 LC-PUFA) have beneficial effects on the obesity-induced metabolic disorders in mice. However, in obese humans, the potency of these fatty acids to positively affect obesity and insulin resistance has been shown to be lower. The aim of the studies described in this thesis was to verify various approaches aimed at increasing efficiency of n-3 LC-PUFA and to study the involvement of 2 subunit of AMP-activated protein kinase (2-AMPK) in the mechanisms of action of these compounds. Firstly, various chemical derivatives of DHA were tested in mice. Substance-2, the -ethyl ester of DHA, completely prevented and even partially reversed the development of obesity, fat accumulation, impaired glucose tolerance, dyslipidemia and white adipose tissue inflammation, even though the dose was only 10 % of that normally used in mice for the treatment with n-3 LC-PUFA. Secondly, the combination of n-3 LC-PUFA and a low-dose of anti-diabetic rosiglitazone prevented, in additive manner, development of dyslipidemia and insulin resistance, reduced the accumulation of body fat and adipocyte hypertrophy, while inducing adiponectin in mice fed a high-fat diet. This treatment also reversed impaired glucose tolerance in obese mice. The major part...
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The role of gut microbiome in the development of type 2 diabetes
Movsesian, Lilit ; Cahová, Monika (advisor) ; Funda, David (referee)
In recent decades, ample evidence of the impact of intestinal microbiota and metabolome on the development of type 2 diabetes and other metabolic disorders such as obesity has been obtained. This thesis provides an overview of known information about this correlation and aims to highlight the importance of further research to identify prospective treatments. Bacterial taxa and metabolites most associated with the incidence of diabetes, as well as those associated with improved glucose and insulin tolerance, are considered. The thesis also compares similarities, differences and contradictions of the discussed studies. Key words: type 2 diabetes, obesity, microbiome, metabolome
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Targeted analysis and metabolism of fatty acids in mice and humans
Oseeva, Marina ; Kuda, Ondřej (advisor) ; Cahová, Monika (referee) ; Vrkoslav, Vladimír (referee)
Widespread sedentary lifestyle and unhealthy eating habits in the last few decades have resulted in a dramatic increase of the number of people affected by obesity, type 2 diabetes, and cardiovascular diseases. The study of these pathological conditions revealed that impaired metabolism often causes these disorders. Lipid metabolism research has contributed significantly to determining mechanisms underlying metabolic disorders. Omega-3 fatty acids are an interesting target for lipidomics studies because they were shown to lower risk of cardiovascular diseases and are hypothesized to regulate lipid metabolism. In this work, I optimized lipid extraction and chemical modification methods for analysis of fatty acids profile of tissue samples and biofluids using comprehensive two-dimensional gas chromatography coupled to mass spectrometry (GCxGC-MS). At first, I evaluated the relative amount of omega-3 fatty acids in red blood cells (Omega-3 index) of people living in Czech Republic in either the capital city (n=476) or the rural region (n=388). For this large-scale project, I extracted phospholipids from red blood cell (RBC) membranes, transesterified them into fatty acid methyl esters (FAMEs), and measured their profile by GCxGC-MS. The mean Omega-3 index was 3.56 mol % and I detected no significant...
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Metabolomics in the study of microbiome
Nazmutdinova, Anastasiia ; Kuzma, Marek (advisor) ; Cahová, Monika (referee)
Inflammatory bowel disease is a serious condition with an incomplete etiology and pathogenesis. In this thesis, a mouse model of sodium dextran sulfate-induced inflammation was used to study different changes in the metabolism of germ-free and conventionally raised mice due to the development of the inflammatory process. NMR metabolomics of fecal, urine and serum samples, combined with uni- and multivariate statistical analysis, were used to characterize the changes. It was shown that the metabolic signature differs between germ-free and conventional mice. In germ-free mice, significant amounts of carbohydrates were found in feces. Their levels decreased during inflammation as they were excreted in urine. In contrast to conventional mice, germ-free mice also excreted large amounts of amino acids in feces during the developing inflammation. Disorders of sugar and protein metabolism found in germ-free mice indicate severe malnutrition caused by inflammation. The results show that the presence of a microbiome represents a protective mechanism against significant disruption in the body. A stability study of fecal extracts of healthy conventionally colonized mice confirmed that none of the identified and quantified metabolites showed significant systemic changes in several consecutively collected...
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Role of adiponectin and B-type natriuretic peptide in the regulation of adipose tissue lipolysis
Wedellová, Zuzana ; Štich, Vladimír (advisor) ; Kunešová, Marie (referee) ; Cahová, Monika (referee) ; Horáková, Olga (referee)
Obesity is a most common metabolic disorder worldwide. Prevalence of obesity is consistently growing in all continents during last years. Primarily the increase of incidence of obesity in children is alarming. Obesity is linked to elevated risk of type 2 diabetes, hyperlipidemia, cardiovascular diseases, some cancers and disorders of musculoskeletal system. The cost of the treatment of diseases linked to obesity is annually increasing and obesity represents very important part of costs of health system in developed - and recently also developing - countries. This fact shows the necessity of research in the area of preventive and therapeutic procedures. The development of metabolic disturbances linked to obesity is associated with dysfunction of adipose tissue. Its two main features are: 1) altered secretion of specific substance with hormonal or paracrinne charakter (called adipokines) and 2) elevated mobilization of non- esterified fatty acids (NEMK) from adipose tissue and subsequently their increased release into the circulation (1). In our studies we paid attention to the study of lipolysis. The rate of lipolysis is the primary factor that determines the release of NEFA from adipose tissue. We focused to a role of adiponectin and natriuretic peptid type B (BNP) in the regulation of lipolysis in...
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Role of immune and adipose cells in the development of adipose tissue inflammation induced by stress associated with obesity
Kračmerová, Jana ; Rossmeislová, Lenka (advisor) ; Cahová, Monika (referee) ; Daňková, Pavlína (referee)
1 SUMMARY Obesity and overfeeding are associated not only with increased circulating levels of nutrients and metabolites, but also with increased risk of the development of additional disorders, such as cardiovascular diseases, cancer or insulin resistance. Plausible link between obesity and its comorbidities is inflammatory state, observed on the whole body level as well as in AT. As possible initiators of this inflammation, hypertrophied adipocytes were suggested. Adipocytes per se secrete a spectrum of heterogeneous molecules including cytokines. Under the stress conditions, adipocytes and subsequently AT resident immune cells switch to pro-inflammatory state and via secretory signaling attract additional immune cells. Furthermore, hypertrophic adipocytes release higher levels of metabolites that may also contribute to pro- inflammatory polarization of immune cells, mainly macrophages. General aim of this thesis was to investigate connection between impaired levels of nutrients and pro-inflammatory statue and activation of immune cells in healthy (obese and lean) subjects. In the Part one of this thesis, we analyzed acute reaction of immune cells in circulation and AT on artificially elevated levels of nutrients, imitating its increased values typical for metabolic syndrome. HFM ingestion led to...
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Regulation of lipogenesis in human adipose tissue: Effect of metabolic stress, dietary intervention and aging.
Šrámková, Veronika ; Rossmeislová, Lenka (advisor) ; Cahová, Monika (referee) ; Kuda, Ondřej (referee) ; Tanti, Jean-Francois (referee)
Adipose tissue (AT) is a complex organ specialised in safe storage and release of energy as lipids. The adipose organ is therefore essential for the maintenance of energy homeostasis. The prototypical cells of AT are adipocytes, emerging from the precursors in a process called adipogenesis. Adipogenesis itself is tightly connected with lipogenesis, i.e. with the synthesis of fatty acids and triglycerides. Various stimuli can disturb adipocyte differentiation and lipogenesis and thus contribute to AT dysfunction and development of associated metabolic diseases. This thesis was endoplasmicfocused on the investigation of lipogenesis in the context of reticulum stress (ERS), calorie restriction and aging. In Project A, we showed that exposition of adipocytes to high acute ERS inhibits expression of lipogenic genes and glucose incorporation into lipids. Moreover, chronic exposure of preadipocytes to ERS impaired both, lipogenesis and adipogenesis. On the other hand, chronic low ERS had no apparent effect on lipogenesis in adipocytes. These effects of ERS could therefore contribute to the worsening of AT function seen in obesity. The capacity of AT to store lipids decreases in aging, possibly due to the accumulation of senescence cells or higher ERS. In Project B, we investigated lipogenic capacity of...
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