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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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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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Investigation of the involvement of central ghrelin signalling in methamphetamine dependence using behavioural and molecular methods
Lapka, Marek ; Šustková, Magdaléna (advisor) ; Votava, Martin (referee) ; Amchová, Petra (referee)
v anglickém jazyce Interest in appetite-inducing peptide hormones, such as ghrelin, is gradually increasing. There is a growing number of publications dealing with the involvement of this orexigenic peptide in the mechanisms of obesity and various addictive behaviours, not excluding addiction to stimulant substances including methamphetamine. Central ghrelin signaling appears to play an important role in addictive behavior, and in the processing of memory traces. Recently, antagonism of the ghrelin receptor for growth hormone secretion (GHS-R1A) has been proposed as a promising tool for the still unsatisfactory treatment of methamphetamine addiction. Premedication with a commonly used experimental GHS-R1A antagonist, the triazole derivative, JMV2959, significantly reduced the rewarding and reinforcing effects of methamphetamine in several animal models of addiction. However, the molecular aspects of GHS-R1A involvement in specific brain regions related to the addiction process remain unclear. This work demonstrates that acute and subchronic (4 days) administration of JMV2959 alone, at doses significantly effective in addiction models (1 and 3 mg/kg intraperitoneally), had no effect on memory functions tested in the Morris water maze in rats, as well as no significant effects on molecular markers...
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The role of ghrelin in modulation of neuropathic pain
Komárková, Lucia ; Vaculín, Šimon (advisor) ; Franěk, Miloslav (referee)
We are still unable to effectively suppress neuropathic pain, therefore it remains a serious problem. Ghrelin, the orexigenic hormone released by enteroendocrine stomach cells, could contribute to alleviation of the neuropathic pain by its antinociceptive effect. Previous studies have shown that ghrelin prevents development of nociceptive symptoms of neuropathic pain. The aim of our study was to determine whether chronic administration of ghrelin will affect the already fully developed neuropathic pain and differentiate its antinociceptive and analgesic effect. We used a model of chronic constriction injury of the sciatic nerve. We have proven that ghrelin suppressed the already developed thermal and mechanical hyperalgesia, so ghrelin not only prevents the development, but also suppresses the already developed nociceptive symptoms. However analgesia test showed that ghrelin did not affect the temperature preference, neither did induce the place preference. We suppose that ghrelin does not cause analgesia in neuropathic pain and its antinociceptive effect could be caused by anti- inflammatory or neuroprotective action. Key words: Ghrelin, neuropathic pain, chronic constriction injury, preference methods
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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...
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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...
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Acipimox during Short-Term Exercise Exerts A Negative Feedback of Growth Hormone on Ghrelin Secretion in Patients with Bulimia Nervosa and in Healthy Women: The Role of Lipolysis
Smitka, Kvido ; Nedvídková, Jara (advisor) ; Kršek, Michal (referee) ; Čáp, Jan (referee)
Title: Acipimox during Short-Term Exercise Exerts A Negative Feedback of Growth Hormone on Ghrelin Secretion in Patients with Bulimia Nervosa and in Healthy Women: The Role of Lipolysis Objective: Eating disorders, such as bulimia nervosa (BN) and anorexia nervosa (AN), are characterized by abnormal eating behavior. The main features of BN are binge-eating and inappropriate compensatory methods to prevent weight gain. The appetite-modulating peptide ghrelin is secreted by the stomach and shows a strong release of growth hormone (GH). A potential GH-ghrelin feedback loop between stomach and the pituitary has been recently reported. Acipimox (Aci), an analogue of nicotinic acid, inhibits lipolysis in adipose tissue (AT) and reduces plasma glycerol and free fatty acids (FFA) levels. Exercise and Aci are stimulators of GH secretion. We suppose that a negative feedback from increased GH levels during exercise may play a role in reducing plasma ghrelin levels. We surmised that altered baseline activity and exercise-induced activation of the sympathetic nervous system (SNS) results in excessive stimulation of lipolysis associated with negative energy balance and may lead to abnormal AT metabolism in patients with BN. Disruption of the gut-brain-AT axis might be involved in the pathogenesis of BN. The...
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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.
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The role of ghrelin in modulation of neuropathic pain
Komárková, Lucia ; Vaculín, Šimon (advisor) ; Franěk, Miloslav (referee)
We are still unable to effectively suppress neuropathic pain, therefore it remains a serious problem. Ghrelin, the orexigenic hormone released by enteroendocrine stomach cells, could contribute to alleviation of the neuropathic pain by its antinociceptive effect. Previous studies have shown that ghrelin prevents development of nociceptive symptoms of neuropathic pain. The aim of our study was to determine whether chronic administration of ghrelin will affect the already fully developed neuropathic pain and differentiate its antinociceptive and analgesic effect. We used a model of chronic constriction injury of the sciatic nerve. We have proven that ghrelin suppressed the already developed thermal and mechanical hyperalgesia, so ghrelin not only prevents the development, but also suppresses the already developed nociceptive symptoms. However analgesia test showed that ghrelin did not affect the temperature preference, neither did induce the place preference. We suppose that ghrelin does not cause analgesia in neuropathic pain and its antinociceptive effect could be caused by anti- inflammatory or neuroprotective action. Key words: Ghrelin, neuropathic pain, chronic constriction injury, preference methods
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