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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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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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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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The analysis of mechanisms associated with beneficial metabolic effects of marine Omega-3 polyunsaturated fatty acids in different lipid forms.
Pavlišová, Jana ; Rossmeisl, Martin (advisor) ; Maletínská, Lenka (referee) ; Cahová, Monika (referee)
Obesity, one of the most serious health problems of the 21st century, often occurs as a result of an imbalance between energy intake and energy expenditure. Dietary lipids play an important role in the development of obesity, partly because they represent the richest source of energy amongst all macronutrients. It is, however, not only the amount of consumed lipids, but also the composition of fatty acids, which strongly influences health effects of a particular diet. Saturated fatty acids (SFA) are generally considered as unhealthy due to their pro-inflammatory and lipotoxic properties, while monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) represent a healthier alternative, as they are more readily oxidized and do not disrupt biochemical properties of cellular membranes. Amongst PUFA, PUFA of n-3 series (Omega-3) represent an utterly unique class of lipids that have been documented to protect against cardiovascular disease and dyslipidemia in men and improve insulin sensitivity and glucose tolerance primarily in animal models of obesity. Some molecular mechanisms of Omega-3 action have been already uncovered, such as the modification of biological membranes composition, activation of various transcription factors and membrane receptors, and their role as precursors for...
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The role of stable analogs of prolactin-releasing peptide in obesity and hypertension.
Neprašová, Barbora ; Maletínská, Lenka (advisor) ; Poledne, Rudolf (referee) ; Rossmeisl, Martin (referee)
Anorexigenic neuropeptides have the potential to decrease food intake and ameliorate obesity and its complications such as high blood glucose or high blood pressure. However, they are not able to cross the blood-brain barrier after peripheral application. Recently, we have designed and synthesized lipidized analogs of prolactin-releasing peptide (PrRP), which resulted in stabilization of the molecule and allowed us to apply the peptide to the periphery to achieve its central biological effect, as it was demonstrated by increased neuronal activity shown by c-Fos in particular hypothalamus nuclei. The aim of this study was to choose the effective dose in acute food intake experiments and then to characterize the subchronic effect of palmitoylated PrRP analogs in mouse and rat models of obesity and diabetes. Several animal models were used: diet-induced obese (DIO) mice (C57Bl/6J), DIO Sprague-Dawley rats, and two rat models with leptin receptor-deficiency: Zucker diabetic (ZDF) rats and spontaneously hypertensive (SHROB) rats. Consumption of a high-fat diet in DIO mice and rats increased their body weight and blood pressure. Two-week intraperitoneal treatment with palmitoylated PrRP31 lowered the food intake, body weight, and returned the blood pressure to normal levels. This treatment also improved...
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Energy metabolism control, selected genetic and hormonal factor
Vejražková, Daniela ; Bendlová, Běla (advisor) ; Rossmeisl, Martin (referee) ; Pelikánová, Terezie (referee)
I I I I I I I 4, CONCLUSIONS r) The postulatedaim of thework was fulfilled: Quite a large cohorts of DM2 patients,direct offspring of DM2 patients,and obese subjectsas well as a group of women suffering from PCOS, and sufficiently large groupof controlsubjectswerecompleted a. All the probands underwenta detailed anthropometricand biochemical characeterization b. The DNA bank was establishedandcompleted An electronicdatabasewas established Molecular geneticmethodsPCR, RFLP, andSSCP wereestablishedandoptimized Specific polymorphismsin the selectedcandidategenes were genotypedand unique data regarding genotypic frequenciesof these polymorphisms in Czech population wereobtained Genetic, biochemical and anthropometric data underwent statistical analysis. Especially associationsbetweengeneticpolymorphisms/adipocytokineconcentrations andanthropometric/biochemicalparametersweretested Final resultswere evaluatedand possibleeffectof the studiedgeneticpolymorphisms and/oradipocytokineson body compositionanďor biochemical statuswas assessed. Also an eventual involvement of the studied genetic and hormonal factors in aethiopathogenesisof obesity,DMZ, metabolicsyndrome,and PCOS was considered Main resultsand conclusionsof theresearchwerepublishedin scientificjournals.The publicationsrepresentthepivotal partof...
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Characterization of metabolic effects of dietary omega-3 fatty acids in transgenic PPARα-humanized mice
Kalendová, Veronika ; Rossmeisl, Martin (advisor) ; Šilhavý, Jan (referee)
Obesity is tightly connected with metabolic diseases including insulin resistance, type 2 diabetes or dyslipidemia. Peroxisome proliferator-activated receptor (PPAR)-α is a key transcription factor involved in the regulation of lipid metabolism, while its activity is stimulated by a variety of hypolipidemic drugs. n-3 polyunsaturated fatty acids (PUFA), including eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid, are endogenous ligands of PPARα, and they are used in the form of fish oil as dietary supplements in order to lower blood lipid levels and to prevent cardiovascular disease. Wax esters represent a novel lipid form of EPA and DHA, and according to recent studies they could exert more potent effects than the classical fish oil (i.e. triacylglycerols). Mice of the 129S1/SvImJ inbred strain were used in the present experiment, and included wild-type (WT) mice, as well as transgenic mice either with the exclusive expression of the human form of PPARα (hPPARα) or mice completely lacking PPARα (PPARα-KO). Mice were fed for 8 weeks the following diets: (i) a control low-fat diet, (ii) obesogenic high-fat diet (cHF), and (iii) the cHF diet supplemented with the n-3 PUFA concentrate in the form of wax esters isolated from marine zooplankton Calanus finmarchicus (ω3Cal). Mice were subjected to...
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Dysregulation of the endocannabinoid system in obesity and its modulation by dietary omega-3 fatty acids
Kalendová, Veronika ; Rossmeisl, Martin (advisor) ; Hlaváčková, Markéta (referee)
Obesity is associated with metabolic complications including insulin resistance, dyslipidemia and hypertension (metabolic syndrome). The endocannabinoid system (ECS) activity is elevated in obesity, which can further potentiate metabolic impairments. Pharmacological treatment based on the cannabinoid receptor CB1 blockade led to a decrease in body weight and significant improvements of metabolic parameters in obese individuals. However, parallel effects on the central nervous system resulted in unwanted side-effects including anxiety and depressive moods. Recent experimental studies suggested that dietary interventions with omega-3 polyunsaturated fatty acids of marine origin (EPA, DHA) can decrease the ECS activity in peripheral tissues (adipose, liver, pancreas), and thus partially protect against metabolic disturbances in obesity. One of the underlying mechanisms behind the effects of EPA and DHA could be a replacement of arachidonic acid from the sn-2 position of membrane phospholipids, thereby reducing the substrate availability for the synthesis of endocannabinoid molecules. Key words: omega-3 fatty acids, obesity, endocannabinoid system, 2-arachidonoylglycerol, anandamide
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