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Mitochondrial ATP synthase deficiencies of a nuclear genetic origin
Karbanová, Vendula ; Houštěk, Josef (advisor) ; Kalous, Martin (referee) ; Rossmeisl, Martin (referee)
ATP synthase represents the key enzyme of cellular energy provision and ATP synthase disorders belong to the most deleterious mitochondrial diseases affecting pediatric population. The aim of this thesis was to identify nuclear genetic defects and describe the pathogenic mechanism of altered biosynthesis of ATP synthase that leads to isolated deficiency of this enzyme manifesting as an early onset mitochondrial encephalo-cardiomyopathy. Studies in the group of 25 patients enabled identification of two new disease-causing nuclear genes responsible for ATP synthase deficiency. The first affected gene was TMEM70 that encodes an unknown mitochondrial protein. This protein was identified as a novel assembly factor of ATP synthase, first one specific for higher eukaryotes. TMEM70 protein of 21 kDa is located in mitochondrial inner membrane and it is absent in patient tissues. TMEM70 mutation was found in 23 patients and turned to be the most frequent cause of ATP synthase deficiency. Cell culture studies also revealed that enzyme defect leads to compensatory-adaptive upregulation of respiratory chain complexes III and IV due to posttranscriptional events. The second affected gene was ATP5E that encodes small structural epsilon subunit of ATP synthase. Replacement of conserved Tyr12 with Cys caused...
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Regulation of adiponectin and its isoforms production in human obesity
Kováčová, Zuzana ; Štich, Vladimír (advisor) ; Hainer, Vojtěch (referee) ; Kazdová, Ludmila (referee) ; Rossmeisl, Martin (referee)
It is apparent that the imbalance in energy intake and expenditure coming hand-to-hand with the "westernisation" of our lifestyle leads to an elevated number of overweight and obese individuals that are commonly in a greater risk of developing chronic complications (e.g. insulin resistance, type 2 diabetes and cardiovascular diseases) with increased mortality. The development of obesity-related complications closely relate with dysfunction of adipose tissue leading to the peripheral insulin resistance and metabolic disruption of insulin sensitive organs (e.g. muscle, liver) subsequently inducing whole body insulin resistance. Since adipose tissue is the biggest endocrine organ in the human body producing many hormones influencing functions of adipose tissue itself or other organs, alteration of their spectrum has been revealed as one of the possible inductors or contributors disturbing body energy homeostasis. Adipose tissue serves as a major site for storage of surplus nutritions, however, long-term positive energy imbalance and high dose calorie intake lead not only to expansion of fat mass but mainly to the pathological changes of the tissue. In states of obesity, adipose tissue is under constant metabolic stress, resulting in the activation of the stress and inflammatory response. It leads to...
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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 effect of dietary n-3 polyunsaturated fatty acids in the regulation of insulin secretion and glucose homeostasis in mice
Doleželová, Šárka ; Rossmeisl, Martin (advisor) ; Neckář, Jan (referee)
Dietary intake of long-chain polyunsaturated fatty acids of n-3 series (n-3 LC-PUFA), especially eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), exert hypolipidemic effect and prevent cardiovascular disease. One of the main targets of n-3 LC-PUFA is adipose tissue, where they activate so called "metabolic switch", resulting in an improvement of lipid and glucose metabolism. In this report, n-3 LC-PUFA suplementation decreased plasma levels of free fatty acids, accumulation of triacylglyceroles in the liver and improved systemic insulin sensitivity in mice fed a high fat diet. There was also a slight decrease in the -cell mass and lower dysfunction of -cells in response to n-3 LC-PUFA feeding. Incretin hormones are secreted from an intestinal cells in response to the ingestion of food, while they also enhance glucose-stimulated insulin secretion. This thesis also analyzed the effect of dietary n-3 LC-PUFA on insulin secretion induced either by the intraperitoneal or oral administration of glucose. The results demonstrated that n-3 LC-PUFA facilitate glucose clearance in response to its oral administration, an effect that is attributable to increased insulin secretion as compared to the effect of intraperitoneal glucose administration. These results suggest that elevated incretin secretion in response...
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Metabolic effects of chronic metformin administration in obese mice depending on the composition of high-fat diet
Roubalová, Jana ; Rossmeisl, Martin (advisor) ; Vybíral, Stanislav (referee)
Obesity leads to many severe metabolic disorders, e.g. dyslipidemia, insulin resistance, ectopic fat accumulation in the liver and skeletal muscles, non-alcoholic fatty liver disease and finally diabetes mellitus type 2. Metformin (1,1-dimethylbiguanide) is the most favored medicament for the treatment and prevention of these disorders. It stimulates cellular glucose uptake and normalizes blood levels of lipid metabolites without triggering insulin secretion. Research on insulin resistance and diabetes is often realized through developing diet- induced obesity in laboratory animals. The aim of this project is to compare metabolic effects of two different high-fat diets named HFD and HSD. The HFD diet consists chiefly of n-6 polyunsaturated fatty acids (corn oil) and starch (100% glucose). The HSD diet contains mainly saturated fatty acids (lard) and sucrose (50% glucose and 50% fructose). I also studied metabolic effects of metformin by adding it continuously to the drinking water given to obese mice fed with the HFD or the HSD diet. Methods: Intraperitoneal glucose tolerance test (IPGTT), blood and tissue levels of lipid metabolites assessment, radio-immunological assessment of blood levels of insulin, assessment of AMPK activity in liver by western blotting. Results: Increased consumption of the...
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Role of adipose tissue in the ethiopatogenesis of insulin resistance
Polák, Jan ; Štich, Vladimír (advisor) ; Hainer, Vojtěch (referee) ; Kazdová, Ludmila (referee) ; Rossmeisl, Martin (referee)
Adipose tissue is involved in etiopathogenesis of insulin resistance and subsequent metabolic disorders including type 2 diabetes mellitus and atherosclerosis. Mechanisms responsible for this association are investigated vigorously. One of the well accepted mechanisms linking excessive accummulation of adipose tissue with a development of insulin resistance are free fatty acids, which are released into circulation after hydrolysis of triglycerides stored in adipose tissue in a process of lipolysis. Impairments in a regulation of lipolysis are described in obese patients and lead to increased plasma level of free fatty acids and to impaired mobilisation of energy stores during exercise. In this PhD thesis, regulation of lipolysis in subcutaneous abdominal adipose tissuewas investigated using microdialysis technique. In the first paper we have observed that dysregulation in catecholamine-induced lipolysis and impaired insulin action in adipose tissue can be improved by dynamic-strength training in obese men. In the second study, we have demonstrated significant involvement of newly discovered lipolytic pathway mediated by atrial natriuretic peptide in lipolysis stimulation during exercise. Adipose tissue is producing several protein substances with regulatory and endocrine functions collectively named...
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