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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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Lipidized analogs of prolactin-releasing peptide as potential agents for obesity therapy: search for mechanism of action
Karnošová, Alena ; Maletínská, Lenka (advisor) ; Žáková, Lenka (referee) ; Janovská, Petra (referee)
Obesity is a common metabolic condition that is becoming more prevalent globally, but current treatments have limitations. Prolactin-releasing peptide (PrRP), a neuropeptide that reduces food intake after administration to the third ventricle, loses this ability when administered peripherally. However, lipidization of peptides enhances their stability in the bloodstream and facilitates their central effect after peripheral administration. We developed lipidized analogs of PrRP, which have high potential as a treatment option for obesity. We previously demonstrated that peripheral administration of lipidized PrRP analogs led to a substantial reduction in food intake and body weight in mice, with palm-PrRP31 and palm11 -PrRP31 emerging as key analogs. In this study, we aimed to further investigate the mechanisms underlying the effects of these two PrRP31 analogs in vitro. Natural PrRP31 binds to its receptor GPR10 and with high affinity to neuropeptide FF receptor type 2 (NPFFR2), which are both expressed in regions involved in food intake regulation. The palmitoylation of PrRP31 increased their binding and agonist properties for both GPR10 and NPFFR2 receptors. Lipidized analogs exhibited a stronger affinity also for another neuropeptide FF receptor, NPFFR1, suggesting that NPFFR1 could be a new potential...
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Molecular basis of deficit of F1Fo-ATP synthase and its impact on energy metabolism of a cell
Štufková, Hana ; Tesařová, Markéta (advisor) ; Kuncová, Jitka (referee) ; Janovská, Petra (referee)
Mitochondria's primary function is to produce energy through the process of oxidative phosphorylation. ATP synthase is a macromolecular rotary machine located in the inner mitochondrial membrane that catalyzes the synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate (Pi). The mitochondrial disorders due to ATP synthase deficiency represent a heterogeneous group of diseases characterized by variable severity of the phenotype with onset at birth or later in life till adulthood. Mutations in both, mitochondrial or nucelar DNA encoded genes, may result in ATP synthase impairment, either isolated or combined with deficits of other complexes of oxidative phosphorylation. The aims of the thesis were to characterize TMEM70 protein, an ATP synthase assembly factor, and to analyze the impact of novel disease variants leading to ATP synthase deficiency in patients' derived samples. TMEM70 is a 21 kDa hairpin structure protein localized in the inner mitochondrial membrane, with both termini oriented into the matrix, which forms higher oligomer structures. Our results demonstrated that the absence of TMEM70 protein leads to an isolated deficiency of complex V followed in some stage by adaptive/compensatory effect of respiratory chain complexes. Different severities...
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Effect of ectopic synthesis of mitochondrial uncoupling protein 1 in white adipose tissue on whole-body metabolism in mice
Janovská, Petra ; Kopecký, Jan (advisor) ; Drahota, Zdeněk (referee) ; Kalous, Martin (referee)
The prevention and treatment of obesity is a major problem of health care systems in affluent societies. Metabolism of adipose tissue belongs to the therapeutical targets, since accumulation of adipose tissue is the basis of obesity development. Experiments using transgenic mice with ectopic expression of brown- fat uncoupling protein 1 (UCP1) in white adipose tissue (WAT), verified a concept that obesity could be ameliorated by increasing energy expenditure in WAT. The goal of the experiments of this PhD Thesis was to characterize in detail the phenotype of this unique animal model of obesity resistance. We have shown that mitochondrial uncoupling in WAT resulted in increased oxidation of fatty acids (FA), in face of decreased lipogenesis and induced mitochondrial biogenesis in this tissue. In further studies, we aimed to modulate propensity to obesity be increasing FA oxidation in WAT in response to physiological stimuli. This could be accomplished in response to the combination treatment using n-3 polyunsaturated fatty acids (n-3 PUFA) and mild calorie restriction in mice fed high-fat diet. Synergistic induction of mitochondrial oxidative capacity and lipid catabolism in epididymal WAT was associated with suppression of low-grade inflammation of WAT, which is typical for obesity. The improvement of lipid...
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Maturation of AMPK in skeletal muscle during early postnatal development
Hansíková, Jana ; Janovská, Petra (advisor) ; Kalous, Martin (referee)
AMP-activated protein kinase (AMPK) is an important metabolic sensor in eukaryotic organisms and it plays an important role in regulating energy homeostasis, at both the cells and the whole organism. AMPK controls glucose and lipid metabolism by direct stimulation of enzymes or by long term stimulation of the gene expression of energy metabolism. Skeletal muscles significantly contribute to the total body weight and metabolic rate and to the maintenance of glucose homeostasis. Due to the ability of the muscle to increase energy expenditure to 95% of whole-body energy expenditure, could be the proper development and programming of metabolism in the early postnatal period crucial for the further development of the organism in adulthood. Early postnatal development leads to substantial changes in energy requirements of the body and this suggests the significant involvement of AMPK in this period. The aim of this thesis was to study the activity and expression of isoforms of the catalytic subunit of AMPK in skeletal muscle during early postnatal development of both mouse strains A/J and C57BL/6 that differ in the development of diet-induced obesity. The next task was to analyze the expression of selected genes involved in energy metabolism - GLUT4, PGC-1α and UCP3 that AMPK regulates. It was found that the...
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Peptides regulating food intake and their lipidized analogs for possible treatment of obesity and cachexia
Buková, Anna-Marie ; Maletínská, Lenka (advisor) ; Janovská, Petra (referee)
In spite of good living conditions, the number of people in the state where the total food intake or individual nutrients is insufficient, unnecessary or unbalanced has increased in recent years. In case of superfluous food intake, amount of fat tissue increases and overweight and obesity appear, which is associated with an increased risk of type 2 of diabetes, cardiovascular disease or certain types of cancer. Insufficient intake of food may, for example, result in the function of the immune system, resulting in an increased risk of infection or poor wound healing. In addition to primary malnutrition, we can see malnutrition as the secondary manifestation of another illness. The state of weight loss and malnutrition caused by another disease is called cachexia. This is a serious complication of primary therapies. At present, in addition to established approaches to the treatment of these diseases, some studies address treatment options using compounds that influence the regulation of food intake. One group of these compounds is peptides able to reduce food intake (anorexigenic peptides) or increase it (orexigenic peptides). To these natural substances in the organism are also sought analogs with properties more favorable for use in practice. One of the possibilities are lipidized analogs, among...
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The role of adipose tissue in the whole-body energy metabolism in mice with different genetic background
Funda, Jiří ; Janovská, Petra (advisor) ; Pecina, Petr (referee) ; Žurmanová, Jitka (referee)
Adipose tissue greatly contributes to the maintenance of the whole-body energy homeostasis. White adipose tissue (WAT) is the most important storage of metabolic energy in the body, while brown adipose tissue (BAT) enables the body to survive in cold environment by transforming metabolic energy to heat. Both WAT and BAT have a critical role in the control of systemic levels of fatty acids, which is necessary for the maintenance of the energy homeostasis and for the prevention of lipotoxic damage of non-adipose tissues. Abundant lipid accumulation can lead to the development of obesity, which is often accompanied by metabolic disorders such as type 2 diabetes and by the impairment of adipose tissue metabolic functions. Healthy adipose tissue prevents from the development of metabolic disorders associated with obesity by buffering the excess of nutrients. The key processes for efficient buffering of fatty acids are futile triacylglycerols/fatty acid cycling (TAG/FA cycling) and fatty acid oxidation. These processes occur in both WAT and BAT and their rates are largely affected by a set of transcriptional regulators, especially peroxisome proliferator-activated receptors (PPARs) and their coactivators. Bioactive molecules such as hormones, polyunsaturated fatty acids (PUFA) or pharmaceutics such as...
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IGF2 and preptin, biologically active peptides derived from pro-IGF2
Mrázková, Lucie ; Žáková, Lenka (advisor) ; Janovská, Petra (referee)
Pro-IGF2 is a 156 amino acid long protein and it is a prohormone from which two bio- logically active peptides are formed, IGF2 and preptin. IGF2 is an insulin-like growth factor 2 that, together with IGF1 and insulin, shares a similar 3-D structure and similar biological effects. It is a peptide whose sequence corre- sponds to amino acids 1-67 of pro-IGF2. It is produced mainly by the liver, but it is formed in most cells of our body. It is involved in the regulation of growth, differentiation, embryogenesis and in recent years the interest in IGF2 has been increasing mainly due to its function in the central nervous system. Preptin is a newly isolated 34 amino acid long peptide whose sequence corresponds to amino acids 69-102 (E-domain) of pro-IGF2. Preptin affects glucose metabolism as well as bone homeostasis. Disorders in glucose metabolism usually lead to diabetes mellitus, and disorders in bone homeostasis most often lead to osteoporosis. Preptin has been shown to increase the second phase of insulin secretion and to have a positive effect on the proliferation and differentiation of osteoblasts, bone cells promoting bone growth. Keywords: pro-IGF2, preptin, IGF2, E-domain, gene expression, imprinting IGF2
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Perivascular adipose tissue in health and disease
Pasáková, Kateřina ; Králová Lesná, Ivana (advisor) ; Janovská, Petra (referee)
Adipose tissue is the biggest endocrine organ in a human body. Its function and composition have been intensively studied due to the rising number of overweight people. The cells of adipose tissue are called adipocytes. The substances that are produced by them are termed adipokines - cytokines secreted by adipocytes. It is possible to distinguish several types of adipose tissue based on its composition - white, brown and transient beige, or based on its location - visceral, subcutaneous and perivascular. Perivascular adipose tissue surrounds most of the blood vessels. Its effect can be inflammatory or anti-inflammatory and it is involved in the process of regulation of vascular tone. Pathology of perivascular adipose tissue can lead to a development of diseases which can directly or indirectly affect the cardiovascular system, and thus it may represent one of the main causes of death in the Western world.
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Peptides regulating food intake and their lipidized analogs for possible treatment of obesity and cachexia
Buková, Anna-Marie ; Maletínská, Lenka (advisor) ; Janovská, Petra (referee)
In spite of good living conditions, the number of people in the state where the total food intake or individual nutrients is insufficient, unnecessary or unbalanced has increased in recent years. In case of superfluous food intake, amount of fat tissue increases and overweight and obesity appear, which is associated with an increased risk of type 2 of diabetes, cardiovascular disease or certain types of cancer. Insufficient intake of food may, for example, result in the function of the immune system, resulting in an increased risk of infection or poor wound healing. In addition to primary malnutrition, we can see malnutrition as the secondary manifestation of another illness. The state of weight loss and malnutrition caused by another disease is called cachexia. This is a serious complication of primary therapies. At present, in addition to established approaches to the treatment of these diseases, some studies address treatment options using compounds that influence the regulation of food intake. One group of these compounds is peptides able to reduce food intake (anorexigenic peptides) or increase it (orexigenic peptides). To these natural substances in the organism are also sought analogs with properties more favorable for use in practice. One of the possibilities are lipidized analogs, among...
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