|
|
New analogues of prolactin-releasing peptide with prolonged effect on food intake
Tichá, Anežka ; Ryšlavá, Helena (advisor) ; Konvalinka, Jan (referee)
Prolactin-releasing peptide (PrRP) is a member of the family of RF-amide peptides. These peptides have typical C-terminal sequence -Arg-Phe-NH2 and similar biological effects. PrRP was discovered as an endogenous ligand of an orphan receptor GPR10 while searching for a factor responsible for a prolactin secretion. This effect was not later confirmed and nowadays, PrRP is mainly considered as an anorexigenic peptide. This is supported by a fact that PrRP and GPR10 deficient mice suffer from hyperphagia and late-onset obesity. Besides GPR10, PrRP is bound to NPFF2 receptor whose endogenous ligand is neuropeptide FF (NPFF). In this study, the PrRP's analogues modified at the N-terminus with fatty acids of different lenghts were tested in vitro on binding and activation MAPK/ERK1/2 signalling pathway. In in vivo experiments on food intake, the central anorexigenic effects of lipidized PrRP-analogues were tested provided their crossing blood brain barrier. Binding studies showed that all analogues bound to rat pituitary RC-4B/C cells with high affinity, analogues containing fatty acid with Ki of one order of magnitude lower than native PrRP. High affinity was also confirmed for binding to cells overexpressing GPR10 receptor and cell membranes with overexpressed NPFF2 receptor. All tested analogues...
|
|
|
Impact of stable ghrelin receptor agonists and antagonists on food intake regulation
Holubová, Martina
The thesis is focused on the effect of ghrelin receptor (GHS-R1a) agonists and antagonist on food intake regulation. Ghrelin is the only known periferally produced orexigenic hormone and the only known acylated hormone. GHS-R1a agonists and antagonists could be useful in the treatment of cachexia and obesity, respectively. In the first part of the thesis, newly designed peptidic GHS-R1a agonists were characterized. The agonists were stabilized by replacing octanoylated Ser3 with a fatty acid coupled to diaminopropionic acid by a stable amide bond. Other noncoded amino acids were also incorporated. Ghrelin analogs were modified by replacing the octanoyl group with another fatty acid, incorporation of the second fatty acid or shortening the peptide chain. Most of the tested GHS-R1a agonists were found to possess high affinities for GHS-R1a (Ki = 10-9 - 10-10 nM) and to activate signaling pathways of ghrelin. After subcutaneous (SC) administration to mice, agonists showed significant and prolonged orexigenic effect. In the second part of the thesis, acute and long-term effects of pseudopeptide GHS- R1a agonist JMV1843 were tested in lean C57BL/6 mice. Acute SC administration of JMV1843 to fed mice increased food intake in a dose-dependent manner (ED50 = 1.94 mg/kg). JMV1843 was stable in blood serum...
|
|
|
New analogs of anorexigenic neuropeptides involved in food intake regulation
Pražienková, Veronika
This work focuses on anorexigenic neuropeptides, cocaine- and amphetamine-regulated transcript (CART) and prolactin-releasing peptide (PrRP), which decrease food intake and body weight. CART peptide is an anorexigenic neuropeptide and, despite many efforts, its receptor has not yet been identified. We found CART peptide specific binding sites in pheochromocytoma PC12 cells. Cells differentiated to neurons increased significantly the number of binding sites. On the other hand, after differentiation to chromaffin cells the number of binding sites was so low that it was impossible to determine their density. To clarify the importance of each of the three disulfide bridges in the CART molecule, analogs with one or two disulfide bridges were synthetized. The biological activity was maintained in analog with two disulfide bridges in positions 74-94 and 88-101. Moreover, we demonstrated the stimulation of JNK and subsequently c-Jun activation in PC12 cells. Neuropeptide PrRP belongs to the RF-amide peptide family and has anorexigenic properties. PrPR has a high affinity to GPR10 and neuropeptide FF (NPFF2) receptor. In our laboratory lipidized analogs of PrRP were synthesized, which are able to decrease food intake after peripheral administration and may cross the blood-brain barrier. We tested biological...
|
|
|
Impact of stable ghrelin receptor agonists and antagonists on food intake regulation
Holubová, Martina ; Maletínská, Lenka (advisor) ; Kopecký, Jan (referee) ; Sobotka, Luboš (referee)
The thesis is focused on the effect of ghrelin receptor (GHS-R1a) agonists and antagonist on food intake regulation. Ghrelin is the only known periferally produced orexigenic hormone and the only known acylated hormone. GHS-R1a agonists and antagonists could be useful in the treatment of cachexia and obesity, respectively. In the first part of the thesis, newly designed peptidic GHS-R1a agonists were characterized. The agonists were stabilized by replacing octanoylated Ser3 with a fatty acid coupled to diaminopropionic acid by a stable amide bond. Other noncoded amino acids were also incorporated. Ghrelin analogs were modified by replacing the octanoyl group with another fatty acid, incorporation of the second fatty acid or shortening the peptide chain. Most of the tested GHS-R1a agonists were found to possess high affinities for GHS-R1a (Ki = 10-9 - 10-10 nM) and to activate signaling pathways of ghrelin. After subcutaneous (SC) administration to mice, agonists showed significant and prolonged orexigenic effect. In the second part of the thesis, acute and long-term effects of pseudopeptide GHS-R1a agonist JMV1843 were tested in lean C57BL/6 mice. Acute SC administration of JMV1843 to fed mice increased food intake in a dose-dependent manner (ED50 = 1.94 mg/kg). JMV1843 was stable in blood serum in...
|
|
|
New analogs of anorexigenic neuropeptides involved in food intake regulation
Pražienková, Veronika ; Maletínská, Lenka (advisor) ; Novotný, Jiří (referee) ; Skálová, Lenka (referee)
This work focuses on anorexigenic neuropeptides, cocaine- and amphetamine-regulated transcript (CART) and prolactin-releasing peptide (PrRP), which decrease food intake and body weight. CART peptide is an anorexigenic neuropeptide and, despite many efforts, its receptor has not yet been identified. We found CART peptide specific binding sites in pheochromocytoma PC12 cells. Cells differentiated to neurons increased significantly the number of binding sites. On the other hand, after differentiation to chromaffin cells the number of binding sites was so low that it was impossible to determine their density. To clarify the importance of each of the three disulfide bridges in the CART molecule, analogs with one or two disulfide bridges were synthetized. The biological activity was maintained in analog with two disulfide bridges in positions 74-94 and 88-101. Moreover, we demonstrated the stimulation of JNK and subsequently c-Jun activation in PC12 cells. Neuropeptide PrRP belongs to the RF-amide peptide family and has anorexigenic properties. PrPR has a high affinity to GPR10 and neuropeptide FF (NPFF2) receptor. In our laboratory lipidized analogs of PrRP were synthesized, which are able to decrease food intake after peripheral administration and may cross the blood-brain barrier. We tested biological...
|
|
|
Příjem potravy, energetická rovnováha, obezita
Polášková, Tereza
This work focuses on food intake, energy balance and obesity. And it gives an overview of the current problems and habits of obesity. In the first part, we focus on energy metabolism, where we focus on energy output and energy intake. In the second part, we begin to look at obesity from a general perspective. Both historical and application of methods to assess obesity. In the following chapters, the etiology, epidemiology, occurrence and causes of obesity are discussed in detail. The last and the biggest part of the thesis deals with treatment, complications associated with obesity and prevention. The aim of this work is to familiarize with food intake, energy balance and obesity. Analyze food intake and energy metabolism, then show the consequences of food intake and this is reflected in the obesity chapter.
|
|
|
Vliv teploty na udržení schopnosti oplození a líhnivosti při přechovávání neoplozených jiker u lína obecného
ANDONIU, Andreas
This theses deals with the storage length of artificially spawn of hard roes of Tench (Tinca tinca) during different temperatures at the time before the semen discharging and activation to fertilization, hatching and consequent survival of fish hatchery throughout changeover from the embryonic to larval life period (beginning of active food intake). Homogeneous assortment of hard roes obtained from hormonally induced artificial hatching of 6 spawners has been used for this experiment. Samples of hard roes were put into plastic bowls and covered, immediately after artificial hatching. Subsequently, they were placed into tempered, thermo-isolating containers with temperatures of 5, 10, 15, 20, 25 and 30 °C. In time intervals of 0.5; 1; 1,5; 2; 3; 4; 6; 8 and 10 hours, a small amount of hard roes were taken away from each temperature (estimated 50 -100 pieces) and put into dry, glass beakers (in 3 repetitions in each temperature combination and length of storage). Subsequently, the semen discharging from 6 milters was carried out and activation by water was performed. Incubation took place in non-sticking environment. During the incubation, or more precisely during the consequent storage of embryos through temperatures between 19-20.5 °C, water was changed daily. Fertilization was evaluated 48 hours after fertilizing. Hatchery was determined 48 hours after beginning of hatching of first specimen. After changeover from embryonic to larval period of ontogenetic development, living food was offered to hatching fish (artemia sp.). Thereafter, the amount of hatched fish with filled intestines was counted. Ascertained values were depicted as a percentage from the total number of seeded hard roes as well as fertilized hard roes with the use of statistic methods (two factors Anovy with the repetition). The highest level (in statistic evaluation on the importance level alfa = 0.05) of hard roe hatchery was accomplished throughout the length of possession and temperature 1 hour/ 25 °C (68.0 +- 3.1 %). The high level of hatchery was maintained by hard roes stored for 2 hours, afterwards a gradual value decrease was registered. Similarly, that was achieved with hatching parameter, where the high level of hatching was achieved with hard roes possessed for the period of 3 hours (except temperature of 30 °C), afterwards the hatchery was decreased. Pursued survival and food intake parameters of hatched fish (from the practical point of view) confirmed above stated dispositions. The high hatchery from placed hard roes was maintained for 1.5 - 3 hours (except 30 °C), thereafter there was its gradual decrease. In the time of 8 hours (temperatures 5 - 20 °C), the survival of 1.2 +- 1.8 %, was found out, with the rest, the survival was nearly zero.
|
|
|
Sleep related neurohumoral regulation of weight management
Havelková, Jarmila ; Tomešová, Jitka (advisor) ; Suchánek, Pavel (referee)
Over the past three decades, it has been confirmed that the alarming increase in number of obese patients is related to the sleep duration and its quality. Neurohumoral response to short sleep duration and poor sleep quality leads to decreased levels of melatonin, leptin and orexin, asto increased levels of cortisol, ghrelin and neuropeptide Y. Such an inaccurate regulation contributes both to excessive intake of energy-dense diet and to the reduction of energy expenditure during physical activity. The bachelor thesis summarizes recent information about the relationship of sleep and obesity, focusing on hormones and peptides involved in the regulation of energy balance processes, including the posssibility to use their mechanisms for weight control.
|
|
|
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...
|
|
|
Impact of circadian system disruption on development of gastrointestinal disorders
Kubištová, Aneta ; Sumová, Alena (advisor) ; Červená, Kateřina (referee)
The ability to sense 24-hour cycles in external environment and to adapt to them is present in a great array of species living on the Earth. Mammals possess internal time-keeping system which is composed of circadian clocks located in the suprachiasmatic nuclei (SCN) of the hypotalamus and peripheral clocks in various tissues and organs of the body. These clocks are adapting to the changes of external environment, such as light and dark cycles or feeding cycles. Peripheral clocks in the organs of the digestive system are synchronized with the signals derived from the central clock in the SCN and also with signals from food intake. Discordance between these signals may result in development of various diseases of the gastrointestinal tract (GIT) related to insufficient digestion or even in higher risk of developing a cancer. This bachelor thesis is generally aimed at circadian rhythms in the body, with the focus on rhythms in the GIT. It will deal with the importance of the circadian rhythms for correct GIT functions. Furthermore, the thesis is focused on connection between the desynchonization of the circadian clock and GIT disease development, namely of obesity and cancer.
|
guest ::
