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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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