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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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Role of Adipokines and Ghrelin in Normal and Nutritionally Modulated Adjuvant Ar thritis in Rats
Štofková, Andrea ; Jurčovičová, Jana (advisor) ; Hainer, Vojtěch (referee) ; Šenolt, Ladislav (referee)
Autoimmune chronic inflammatory diseases, affecting as much as 5-7% of the general population, represent a considerable portion of human morbidity and many are known to be heritable. The clinical observations strongly suggest that even in genetically predisposed person, some trigger (an environmental exposure or change in the internal environment) is required for initiation of autoreactivity. However, for most autoimmune diseases, the trigger is unknown. Over the last decade, it has become apparent that obesity is an enhancer of chronic inflammation, and white adipose tissue products - adipokines and gastric hormone ghrelin have attracted attention for their immunomodulatory roles representing promising avenues for pharmacotherapy of autoimmune chronic inflammatory diseases. The purpose of this dissertation was to extend our understanding of the roles of adipokines and ghrelin in chronic inflammation using an experimental model of rheumatoid arthritis, adjuvant arthritis (AA) in rats. The chronic inflammation was studied under the condition of (a) normofeeding, (b) overfeeding (using a model of early-life diet-induced obesity, comprising small litter size and high-fat diet consumption) and (c) 40% foodrestriction to reveal to what extent nutritional factors affect adipokine and ghrelin levels and...
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Sickness behaviour in the early adjuvant arthritis (role of neuroinflamation and oxidative stress?)
Škurlová, Martina ; Jurčovičová, Jana (advisor) ; Šterzl, Ivan (referee) ; Paleček, Jiří (referee)
Background: Rheumatoid arthritis is an inflammatory autoimmune polyarthritis. Although, it is not a CNS involvement disease, affective disorders and alterations of cognitive functions occur in rheumatic patients and may vary in their relevance from serious psychosis to memory disorders. Aetiology of sickness behaviour in arthritis is not known yet. Aims: The aim of the present work was to study incidence of behavioural components of sickness in the early phase of experimental arthritis, and to confirm an association between behavioural components of sickness and neuro- inflammatory / chemical alterations in the hippocampus in this phase of the disease. Methods: Experimental arthritis was induced to Lewis rats by a single injection of cFA. First four days of experimental arthritis were studied. The body weight and food intake were measured daily. Pain reactivity, behaviour and biochemical analysis in plasma and hippocampus were done on day 2 and on day 4. Pain reactivity was measured separately on limbs and on tail in plantar test. Spatial learning abilities and swim strategies were examined in MWM. Anxiety behaviour was tested in EPM and open field tests. In plasma, concentration of CRP, albumin, ACTH, corticosterone, leptin, ghrelin were estimated. In hippocampus, mRNA gene expression of IL-1β, IL-...
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Impact of leptin and ghrelin on food intake and metabolic parameters in obese ovariectomized female mice
Matyšková, Resha ; Maletínská, Lenka (advisor) ; Jurčovičová, Jana (referee) ; Kuneš, Jaroslav (referee)
The thesis is focused on the effect of leptin and ghrelin receptor antagonists on food intake and metabolic parameters in ovariectomized (OVX) female mice on a high fat (HF) diet. In the first part of the thesis, diet-induced obesity was introduced in two strains of mice (NMRI and C57BL/6). Diet-induced obesity resulted from overconsumption of a HF diet containing 60 % of fat; a standard (St) diet contained only 9 % of fat. The strain C57BL/6 was more susceptible to a HF diet than the NMRI strain and was chosen for further experiments on food intake. In the second part of the thesis, OVX C57BL/6 female mice on a HF diet were introduced as a model of common obesity in women after menopause and overconsumption of high caloric food. OVX mice on a HF diet accumulated more than 4 times higher amount of the white adipose tissue compared to those on a St diet, had significantly elevated glucose, insulin and leptin levels and attenuated sensitivity to effect of centrally administered leptin, an adipokine that decreases food intake. Central leptin sensitivity and metabolic syndrome parameters were improved after 4 weeks of estradiol treatment. Because both ovariectomy and HF diet result in enhanced sensitivity to ghrelin, the hormone produced predominantly by the stomach that stimulates appetite, in the...
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Sickness behaviour in the early adjuvant arthritis (role of neuroinflamation and oxidative stress?)
Škurlová, Martina ; Jurčovičová, Jana (advisor) ; Šterzl, Ivan (referee) ; Paleček, Jiří (referee)
Background: Rheumatoid arthritis is an inflammatory autoimmune polyarthritis. Although, it is not a CNS involvement disease, affective disorders and alterations of cognitive functions occur in rheumatic patients and may vary in their relevance from serious psychosis to memory disorders. Aetiology of sickness behaviour in arthritis is not known yet. Aims: The aim of the present work was to study incidence of behavioural components of sickness in the early phase of experimental arthritis, and to confirm an association between behavioural components of sickness and neuro- inflammatory / chemical alterations in the hippocampus in this phase of the disease. Methods: Experimental arthritis was induced to Lewis rats by a single injection of cFA. First four days of experimental arthritis were studied. The body weight and food intake were measured daily. Pain reactivity, behaviour and biochemical analysis in plasma and hippocampus were done on day 2 and on day 4. Pain reactivity was measured separately on limbs and on tail in plantar test. Spatial learning abilities and swim strategies were examined in MWM. Anxiety behaviour was tested in EPM and open field tests. In plasma, concentration of CRP, albumin, ACTH, corticosterone, leptin, ghrelin were estimated. In hippocampus, mRNA gene expression of IL-1β, IL-...
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Role of Adipokines and Ghrelin in Normal and Nutritionally Modulated Adjuvant Ar thritis in Rats
Štofková, Andrea ; Jurčovičová, Jana (advisor) ; Hainer, Vojtěch (referee) ; Šenolt, Ladislav (referee)
Autoimmune chronic inflammatory diseases, affecting as much as 5-7% of the general population, represent a considerable portion of human morbidity and many are known to be heritable. The clinical observations strongly suggest that even in genetically predisposed person, some trigger (an environmental exposure or change in the internal environment) is required for initiation of autoreactivity. However, for most autoimmune diseases, the trigger is unknown. Over the last decade, it has become apparent that obesity is an enhancer of chronic inflammation, and white adipose tissue products - adipokines and gastric hormone ghrelin have attracted attention for their immunomodulatory roles representing promising avenues for pharmacotherapy of autoimmune chronic inflammatory diseases. The purpose of this dissertation was to extend our understanding of the roles of adipokines and ghrelin in chronic inflammation using an experimental model of rheumatoid arthritis, adjuvant arthritis (AA) in rats. The chronic inflammation was studied under the condition of (a) normofeeding, (b) overfeeding (using a model of early-life diet-induced obesity, comprising small litter size and high-fat diet consumption) and (c) 40% foodrestriction to reveal to what extent nutritional factors affect adipokine and ghrelin levels and...
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Impact of leptin and ghrelin on food intake and metabolic parameters in obese ovariectomized female mice
Matyšková, Resha ; Maletínská, Lenka (advisor) ; Jurčovičová, Jana (referee) ; Kuneš, Jaroslav (referee)
The thesis is focused on the effect of leptin and ghrelin receptor antagonists on food intake and metabolic parameters in ovariectomized (OVX) female mice on a high fat (HF) diet. In the first part of the thesis, diet-induced obesity was introduced in two strains of mice (NMRI and C57BL/6). Diet-induced obesity resulted from overconsumption of a HF diet containing 60 % of fat; a standard (St) diet contained only 9 % of fat. The strain C57BL/6 was more susceptible to a HF diet than the NMRI strain and was chosen for further experiments on food intake. In the second part of the thesis, OVX C57BL/6 female mice on a HF diet were introduced as a model of common obesity in women after menopause and overconsumption of high caloric food. OVX mice on a HF diet accumulated more than 4 times higher amount of the white adipose tissue compared to those on a St diet, had significantly elevated glucose, insulin and leptin levels and attenuated sensitivity to effect of centrally administered leptin, an adipokine that decreases food intake. Central leptin sensitivity and metabolic syndrome parameters were improved after 4 weeks of estradiol treatment. Because both ovariectomy and HF diet result in enhanced sensitivity to ghrelin, the hormone produced predominantly by the stomach that stimulates appetite, in the...
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