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Interplay between ghrelin and its novel endogenous antagonist LEAP2: possible role in the pathology of obesity
Holá, Lucie ; Maletínská, Lenka (advisor) ; Jurčovičová, Jana (referee) ; Malínská, Hana (referee)
The increasing number of overweight and obese individuals has become a major health issue in our society. The etiology of obesity often involves excessive hyperphagia, highlighting the importance of comprehensive understanding the regulation of food intake regulation in order to effectively treat this chronic condition. Ghrelin, a peripheral peptide hormone responsible for increasing food intake, directly affects the hypothalamus through the growth hormone secretagogue receptor (GHSR). Recently, it was found that liver expressed antimicrobial peptide 2 (LEAP2) naturally counteracts the effects of the GHSR as an inverse agonist. This makes LEAP2 a potential candidate for the development of anti-obesity treatment. This thesis explores the interaction between ghrelin and LEAP2 in the context of food intake regulation and obesity. Firstly, it focuses on modified N-terminal peptide LEAP2(1-14) and its lipidized analogs, examining their affinity to and activation of GHSR in vitro and in vivo. The results demonstrate that palmitoylated LEAP2(1-14) (palm-LEAP2(1-14)) exhibits the most pronounced affinity for GHSR, acts as GHSR inverse agonist, reduces food intake, inhibits growth hormone release, and shows increased stability in rat plasma. These findings suggest that palm-LEAP2(1-14) holds promise as an...
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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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Effects of ghrelin and its novel endogenous antagonist LEAP2 and their role in obesity
Tureckiová, Theodora ; Maletínská, Lenka (advisor) ; Selicharová, Irena (referee)
Obesity is a very dangerous metabolic disease, caused by the development of resistance to the anorexigenic (food intake reducing) hormone leptin, with an ever-increasing prevalence. Recently, both anorexigenic peptides and orexigenic (food intake increasing) peptide antagonists have emerged as candidates for the development of anti-obesity treatment. An example of such a peptide is the newly discovered endogenous ghrelin antagonist known as liver enriched antimicrobial peptide 2 (LEAP2). The uniqueness of the relationship between ghrelin and LEAP2 lies in the unusual occurrence of agonists and antagonists of the same receptor within the same organism. This receptor, known as growth hormone secretagogue receptor 1a (GHSR1a), is, among other roles, responsible for increased food intake and weight gain. Natural ghrelin and LEAP2 analogues, specifically non-lipidized LEAP2(1-14) fragment and lipidized (palmitoylated) palm-LEAP2(1-14) were used for studying their properties. The aim of this study was to demonstrate binding properties of LEAP2 analogues to the GHSR1a and to compare the effect of the lipidized analogue versus the non- lipidized one in vitro. Effects of the lipidated analogue were further investigated in vivo. Results of in vitro experiments demonstrated the binding of both LEAP2 analogues...
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Peptides regulating food intake and their role in metabolic syndrome
Buderová, Markéta ; Maletínská, Lenka (advisor) ; Hojná, Silvie (referee)
Unhealthy lifestyle together with genetic factors can lead to serious health problems like metabolic syndrome (MetS). MetS is a cluster of risk factors such as abdominal obesity, dyslipidemia, insulin resistance and hypertension. Each component of MetS contributes to cardiovascular diseases, type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease. Treatment of MetS is primarily focused on lifestyle modification, especially weight loss. In severe cases, pharmacological treatment is also used. Pharmacological treatment includes peptide analogues that regulate food intake. Anorexigenic (food- reducing) peptides are involved in the regulation of food intake, together with orexigenic (food- increasing) peptides, which thus play an important role in maintaining energy homeostasis. Several analogues of anorexigenic peptides regulating food intake are already used for the treatment of obesity or T2DM. Other peptide analogues are in preclinical stages of testing or in the development of stable analogues. Elucidating the physiology and pathology of both anorexigenic and orexigenic peptides in the regulation of food intake may contribute to finding potential treatments for metabolic, cardiovascular, and other disorders.
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Neuroprotective effects of novel anorexigenic analogs of prolactin-releasing peptide (PrRP) in models of neurodegeneration in vitro and in vivo
Mengr, Anna ; Maletínská, Lenka (advisor) ; Sumová, Alena (referee) ; Hampl, Aleš (referee)
Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular beta amyloid (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Since obesity and type 2 diabetes mellitus (T2DM) have been established as risk factors for the development of neurological disorders, anorexigenic and antidiabetic peptides, such as prolactin-releasing peptide (PrRP) seem to be potential neuroprotective agents. In the first part of the study, the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm11 -PrRP31 was studied in the human neuroblastoma cell line SH-SY5Y. Both compounds significantly activated the signaling pathways typical for insulin promoting cell survival and growth. Moreover, PrRP31 and palm11 -PrRP31 increased cell viability and suppressed apoptosis in methylglyoxal-stressed SH-SY5Y cells. The second part of the thesis was focused on the neuroprotective and anti-inflammatory effects of 2-month-long subcutaneous administration of palm11 -PrRP31 in the brains of APP/PS1 mice, model of Aβ pathology. Palm11 -PrRP31 significantly reduced the Aβ plaque load and microgliosis in the hippocampi, cortices, and cerebella. Furthermore, palm11 -PrRP31 increased the synaptogenesis and attenuated...
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Effects of stable analogs of anorexigenic neuropeptides in models of metabolic syndrome
Mráziková, Lucia ; Maletínská, Lenka (advisor) ; Kříž, Jan (referee) ; Bardová, Kristina (referee)
Obesity is a worldwide health problem and an effective treatment is still scarce. Anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential for the treatment of obesity and its complications, but in their natural form they have several limitations such as poor bioavailability, low stability and inability to cross the blood-brain barrier after peripheral administration. Recently we have designed lipidized analogs of PrRP. Lipidization makes this peptide more stable and able to act centrally after peripheral administration. The aim of this study was to investigate the chronic effect of PrRP palmitoylated at position 11 (palm11 -PrRP31) on obesity and obesity-related metabolic parameters and to clarify mechanisms of its action. We used three rodent models of obesity: Wistar Kyoto (WKY) rats with high-fat diet-induced obesity (DIO) having intact leptin and leptin receptor as well as rodents with disrupted leptin function: leptin deficient ob/ob mice and fa/fa rats with a disturbed leptin signaling. Consumption of a high-fat diet in DIO WKY rats increased their body weight, caused strong glucose intolerance and increased liver mRNA expression of enzymes of de novo lipogenesis. Palm11 -PrRP31 treatment significantly decreased cumulative food intake, body weight, plasma...
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New pharmacological interventions influencing food intake focused on effects of CART (cocaine- and amphetamine-regulated transcript) peptide and prolactin-releasing peptide
Maixnerová, Jana ; Maletínská, Lenka (advisor) ; Zorad, Štefan (referee) ; Skálová, Lenka (referee)
The thesis was focused on characterization of biological activities of two recently discovered anorexigenic neuropeptides: CART (cocaine- and amphetamine-regulated transcript) peptide and prolactin-releasing peptide (PrRP). In order to find a pharmacophore of CART peptide, shorter fragments of CART(61- 102) peptide were tested for binding to PC12 cells and inhibition of food intake in fasted mice. The results showed that a compact structure of CART peptide containing three disulphide bridges is necessary for preservation of its full biological activity. In the second part of the thesis, synergistic and long-lasting effect of centrally administered peptide CART and peripherally administered cholecystokinin (CCK) is described. In fasted C57BL/6 mice, the anorexigenic effect of CART was enhanced by a subthreshold dose of CCK, while CCK1 receptor antagonist devazepide blocked the effect of CART peptide on food intake. In the third part of the thesis, food intake in fed lean and MSG (monosodiumglutamate treated) obese male mice with lesions in nucleus arcuatus (ARC) was followed. Anorexigenic action of CART peptide was preserved but satiety effect of CCK was completely lost in MSG obese mice and therefore, effective leptin signaling in ARC is necessary for satiety effect of CCK. Finally, the PrRP...
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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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