Es wurde das Hormon Ghrelin im Speichel, der Sulkusflüssigkeit und im Blut bei Parodontitis und unterschiedlichem Körpergewicht untersucht. Geklärt werden sollte, ob Ghrelin ein Parodontitismarker sein kann.:I Abkürzungsverzeichnis IV II Tabellenverzeichnis VII III Abbildungsverzeichnis VIII 1. Einleitung 1 1.1 Ghrelin 1 1.1.1 Aufbau und Produktion 1 1.1.2 Funktion 4 1.2 Speichel 8 1.2.1 Aufbau und Produktion 8 1.2.2 Funktion 10 1.2.3 Speichel und Ghrelin 11 1.3 Sulkusflüssigkeit 13 1.3.1 Produktion und Funktion 13 1.3.2 Sulkusflüssigkeit und Ghrelin 14 1.4 Blutserum 15 1.4.1 Aufbau und Funktion 15 1.4.2 Serum und Ghrelin 15 1.5 Parodontitis und Abwehr 16 1.6 Körpergewicht und Entzündung 18 2. Ziele der Studie 20 3. Methoden/ Experiment 21 3.1 Patientenkollektiv 21 3.1.1 Einschlusskriterien 21 3.1.2 Ausschlusskriterien 22 3.1.3 Ethikantrag und Menschenrechtskonvention 22 3.2 Klinische Variablen 23 3.2.1 Bestimmung des Body-Mass-Index 23 3.2.2 Bestimmung des Approximalraum-Plaqueindex 23 3.2.3 Bestimmung des Sulkusblutungsindex 24 3.2.4 Bestimmung des Bluten auf Sondieren 24 3.2.5 Erhebung der Sondierungstiefen und Attachmentlevel 25 3.3 Gewinnung der Proben 26 3.3.1 Gewinnung von Speichel 26 3.3.2 Gewinnung von Sulkusflüssigkeit 26 3.3.3 Gewinnung von Blut 26 3.4 Untersuchung der Proben 27 3.4.1 Quantitative Ghrelinbestimmung durch enzymgekoppelten Immunadsorptionstest (ELISA) 27 3.4.2 Statistische Methoden 28 4. Ergebnisse 30 4.1 Gruppeneinteilung 30 4.2 Demografische und klinische Daten 32 4.3 Gruppenvergleiche 34 4.3.1 Parodontitis vs. parodontal gesund / Gingivitis 34 4.3.2 Parodontitis übergewichtig vs. normalgewichtig 36 4.3.3 Gesund / Gingivitis übergewichtig vs. normalgewichtig 38 4.3.4 Parodontitis übergewichtig vs. gesund / Gingivitis übergewichtig 40 4.3.5 Parodontitis normalgewichtig vs. gesund / Gingivitis normalgewichtig 42   5. Diskussion 44 5.1 Methoden und klinische Durchführung 44 5.2 Bewertung und Beurteilung der Ergebnisse 45 6. Zusammenfassung 56 7. Literaturverzeichnis 60 8. Anhang 75 8.1 Anamnesebogen 76 8.2 Einwilligungserklärung 77 8.3 Formblatt Parodontalstatus 79 8.4 Tabelle Patientendaten und Ergebnisse 80 9. Selbständigkeitserklärung 82 10. Lebenslauf 83 11. Publikationen 84 12. Danksagung 85

Ghrelin is a hormone produced mainly by the cells lining the gastric mucosa. Ghrelin was first extracted from human and rat stomachs, and identified as an endogenous stimulator of growth hormone release. Ghrelin is synthesized and produced in several tissues, but the gastric mucosa remains the major source of circulating ghrelin. Besides growth hormone release, ghrelin stimulates appetite and plays some major roles in different organs. In several studies, ghrelin was described as a hormone with multiple functions and diverse biological actions. Ghrelin exists in two major forms, active ghrelin and inactive ghrelin, and only the active from binds to the receptor. The majority of total circulating ghrelin is inactive ghrelin with no identified function. The aims of the present study were to measure active and total ghrelin in dairy cow’s milk and plasma during early lactation, and to observe changes in the ghrelin concentrations over time. We are interested in this period of time since the milk during early lactation contains a variety of biologically active hormones that are vital for newborn calves. In this study, fifteen Holstein dairy cows were selected randomly from different lactations. Milk and blood samples were taken daily from cows at early lactation for 10 days, and from some cows in mid-lactation. A laboratory test was used to measure active and total ghrelin in milk and plasma samples. Supplementary measurements such as milk fat, lactose, protein, and milk yield were recorded. Active and total milk ghrelin concentrations were found to be significantly higher in the first day of lactation during colostrum production. Interestingly, the percentage of active to total ghrelin in milk and blood was constant in all days tested, suggesting that this constant percentage can be used to estimate active or total ghrelin, if one of them is know, from the same sample. However, no correlation was observed between the percentage of milk ghrelin and plasma ghrelin or with other milk components. In conclusion, the presence of ghrelin in colostrum and milk in measurable amounts of both active and total form suggests that it is a critical compound for the metabolic activity of newborn calves and functions transiently to regulate the activity of some physiological processes until the endocrine system of the new calves starts to function independently.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第18197号 / 人健博第14号 / 新制||人健||2(附属図書館) / 31055 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 藤井 康友, 教授 岡 昌吾, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(人間健康科学) / 乙第13064号 / 論人健博第3号 / 新制||人健||3(附属図書館) / (主査)教授 高桑 徹也, 教授 三谷 章, 教授 横出 正之 / 学位規則第4条第2項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21148号 / 農博第2274号 / 新制||農||1058(附属図書館) / 学位論文||H30||N5122(農学部図書室) / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 金本 龍平, 教授 保川 清, 教授 谷 史人 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

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Bakgrund En mer stillasittande livsstil med ett högre kaloriintag ökar riskerna för övervikt och andra metabola sjukdomar. För att förebygga och behandla dessa sjukdomar behöver vi bland annat förstå hur hungerkänslor regleras hos människan. Hur stor inverkan blodglukosnivåer har på hungerregleringen är dock omdiskuterat. Syfte Syftet med denna studie var att undersöka hur hungerkänslor och blodglukosnivåer förändras efter en måltid, jämfört med fasta. Kan den upplevda hungern påverkas genom periodisk fas-ta? Hur påverkar en invand måltidsrytm hungern? Hur påverkas hunger och blodglukos i för-väntan på en måltid? Metod Tolv friska testpersoner (7 män, 5 kvinnor) där sju stycken var vana vid periodisk fasta och fem inte var det, randomiserades in i två grupper där ena gruppen (Pi) fick äta en 600 kcal pizza medan den andra gruppen fick fasta (F). Blodglukosvärden och hungeruppskattningar registrerades var 30:e minut, förutom första värdet som registrerades 15 minuter innan pizzor-na serverades. Testpersonerna visste inte vilken grupp de skulle hamna i förrän 10 minuter innan pizzorna serverades. Resultat Fem timmar efter måltiden kunde ingen signifikant skillnad i blodglukossänkning observeras mellan grupperna. Hungern skiljde sig inte heller signifikant mellan grupperna. Endast Pi ökade dock signifikant i hunger (P = 0,05) jämfört med sina startvärden. Fastevana bidrog inte till en förbättrad hungerkontroll. Beskedet om vilken grupp testpersonerna skulle hamna i resulterade i att blodglukosnivåerna skiljde sig signifikant mellan grupperna (P = 0,05) när pizzorna serverades. Då sänktes blodglukosnivåerna hos Pi samtidigt som de höjdes hos F. Fyra av fem testpersoner i F och en testperson i Pi blev tydligt hungrigare vid tidpunkter då de vanligtvis brukade äta på. Slutsats Samband mellan absoluta blodglukosnivåer och hunger kunde inte hittas. Stark hunger kunde uppstå fastän dietär energi sannolikt fortfarande absorberades i tarmarna.Våra resultat indikerade därför att akut energitillgänglighet utgör en relativt liten del i den totala hungersignaleringen. En invand måltidsrytm såg ut att påverka hungern mer än vad måltiden i den här studien gjorde. Större fokus vid hungerreglering bör därför ligga på en re-gelbunden måltidsrytm. / Background The increasingly sedentary lifestyle of our society combined with a constantly rising caloric intake has elevated the risk of developing obesity and other metabolic diseases. There is a need to understand the underlying mechanisms of hunger regulation to effectively prevent and treat these diseases. The magnitude of which an active regulation of blood glucose has an influence on hunger regulation is rather controversial. Objective The objective of this study was to investigate how the changes in hunger and blood glucose levels may differ after a mixed meal compared to the fasting state. Research questions include: Does intermittent fasting reduce general hunger? How does an entrenched meal-pattern affect hunger? How does hunger and blood glucose change in anticipation of a meal? Method Twelve healthy subjects (7 men, 5 women), of which seven subjects regularly practiced intermittent fasting and the remaining five did not, were randomized into two groups, one group was eating pizza (Pi), and the other group was fasting (F). Blood glucose levels and hunger ratings were collected every 30 minutes, with exception of initial values that were collected 15 minutes prior to the serving of the pizzas. The subjects were unaware of which group they would be designated to until 10 minutes prior to the serving of the pizzas. Results Decline in blood glucose did not significantly differ between groups during the 5 hour window following the meal ingestion. Hunger ratings differed significantly between individuals but not between groups. However, only Pi had significantly elevated hunger ratings in the end of the test period compared to their initial ratings. In anticipation of the meal a significant change in blood glucose was observed between the groups (P = 0.05), where values dropped for Pi and rose for F. Four out of five subjects in F and one subject in Pi were considerably hungrier during time periods they reported as habitual eating occasion. Conclusion Correlations between absolute blood glucose levels and hunger could not be found. An equal rise in hunger appear regardless if subjects were fed or fasting, meaning significant hunger can appear although dietary energy still is absorbed into the blood stream. Thus our results indicate that the acute availability of dietary energy is only a relatively small part of the total hunger signaling process. A disrupted meal pattern seemed to affect hunger feelings more than the ingestion of the served meal. Thus we conclude that more research should focus on meal-pattern regulation to enable better hunger control.

Background: The appetite-stimulating hormone ghrelin is a fundamental regulator of human energy metabolism. A series of studies support the notion that long-term appetite and weight regulation may be already programmed in early life and it could be demonstrated that the intrauterine environment affects the ghrelin system of the offspring. Animal studies have also shown that intrauterine programming of orexigenic systems persists even until adolescence/adulthood. Methods: We hypothesized that plasma ghrelin concentrations in adulthood may be associated with the intrauterine exposure to cigarette smoke. We examined this hypothesis in a sample of 19-year-olds followed up since birth in the framework of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study of the long-term outcome of early risk factors. Results: As a main finding, we found that ghrelin plasma concentrations in young adults who had been exposed to cigarette smoke in utero were significantly higher than in those without prenatal smoke exposure. Moreover, individuals with intrauterine nicotine exposure showed a significantly higher prevalence of own smoking habits and lower educational status compared to those in the group without exposure. Conclusion: Smoking during pregnancy may be considered as an adverse intrauterine influence that may alter the endocrine-metabolic status of the offspring even until early adulthood.

In recent years there has been growing interest in the role of gut hormones in regulating appetite, energy balance and weight control. Prominent among these hormones is the hunger hormone ghrelin which is the only circulating hormone currently known to stimulate appetite. A variety of hormones are known to suppress appetite and notable among these is peptide YY (PYY). Both ghrelin and PYY exist in more than one form with acylated ghrelin and PYY3-36 representing the biologically active forms of these hormones i.e. the form of each hormone with the most potent effects on appetite. Many studies have investigated ghrelin responses to exercise in male participants and some studies have also examined PYY responses. Far fewer studies have examined ghrelin and PYY responses in female participants and this was the primary purpose of the studies reported here. This thesis comprises four main experimental chapters which collectively sought to clarify whether there is any evidence to support the hypothesis that appetite, gut hormone and food intake responses differ in female compared with male participants. A total of 123 participants took part in the studies reported in this thesis. The first of these studies was cross-sectional in nature and compared fasting appetite, plasma acylated ghrelin and dietary restraint questionnaire values (among other variables) in 34 males and 33 females. No significant differences were observed between sexes for any of these variables. In the second study, appetite, plasma acylated ghrelin and ad libitum food intake responses to cycling exercise were examined in 13 female participants taking the oral contraceptive pill in both the luteal and follicular phases of the menstrual cycle. Although fasting hunger and prospective food consumption values were higher in the follicular than the luteal phase there was no difference in appetite, plasma acylated ghrelin and food intake responses to exercise between menstrual cycle phases. In the third study, appetite, plasma acylated ghrelin, plasma PYY3-36 and food intake responses to energy deficits created via diet and exercise were compared in 13 young, healthy female participants who completed three separate trials (control, exercise deficit and food deficit) in a random order. The findings revealed that, as with male participants, females experience compensatory appetite, gut hormone and food intake responses to dietary induced energy deficits but not to exercise induced energy deficits (over the course of a nine hour observation period). The final study reported in this thesis compared appetite, plasma acylated ghrelin and ad libitum food intake responses to a one hour run in 10 male and 10 female participants. Suppressions of both hunger and plasma acylated ghrelin were noted during exercise but there was no significant difference in the responses of males and females during or after exercise. Collectively, the studies reported here suggest: 1) that fasting appetite and plasma acylated ghrelin concentrations do not differ between male and female participants; 2) that appetite, ghrelin and food intake responses to cycling exercise do not differ according to the phase of the menstrual cycle in females; 3) that dietary restriction is more likely to elicit compensatory feeding responses than elevated exercise levels in females and 4) that males and females do not differ in their acute appetite, ghrelin and food intake responses to an acute bout of running exercise. Hence the studies reported here do not support the hypothesis that exercise will be less effective for controlling appetite and food intake in females than in males.

La ghréline, une hormone peptidique principalement synthétisée au niveau de l'estomac, est le ligand endogène du récepteur des sécrétagogues de l'hormone de croissance appelé GHS-R1a. Elle est impliquée dans de nombreux processus biologiques dont principalement la sécrétion de l'hormone de croissance et la régulation de l'homéostasie énergétique. En raison de ses propriétés orexigènes et adipogènes, la ghréline est un outil puissant pour lutter contre les déséquilibres énergétiques. Développer des antagonistes de son récepteur représente ainsi une stratégie prometteuse pour la découverte de nouvelles pharmacothérapies contre l'obésité.Cette thèse est consacrée au développement d'antagonistes du récepteur de la ghréline dont la structure est basée sur une plateforme peptidomimétique : le 1,2,4-triazole 3,4,5-trisubstitué. Notre objectif est de concilier au mieux l'affinité et l'activité de nos ligands vis-à-vis du GHS-R1a avec des propriétés optimisées permettant de favoriser une bonne biodisponibilité orale. Nous nous sommes basés sur une synthèse rapide et efficace de ces composés pour réaliser des études approfondies de relations structure-activité et structure-propriété. En optimisant successivement les différentes positions autour du motif triazole, des compromis intéressants ont été obtenus. Nous avons ainsi identifié des antagonistes affins du récepteur qui présentent une stabilité microsomale suffisante et une perméabilité membranaire satisfaisante pour envisager des études in vivo. / Ghrelin, a peptidic hormone which is mainly synthesized in the stomach, is the endogenous ligand of the growth hormone secretagogue receptor named GHS-R1a. It is involved in numerous biological processes such as the growth hormone secretion and the control of energy homeostasis. Because of its orexigenic and adipogenic properties, ghrelin is a potent tool to control energy imbalance. Developing ghrelin receptor antagonists represents a promising strategy for the discovery of anti-obesity new drugs.This thesis is devoted to the development of ghrelin receptor antagonists based on a peptidomimetic scaffold: the 3,4,5-trisubstituted 1,2,4-triazole. Our aim is to combine ligand affinity and activity towards GHS-R1a with optimized properties which enable to promote a good oral bioavailability. We based our work on a rapid and efficient synthesis of our compounds to carry out detailed structure-activity and structure-property studies. By successively optimizing the different positions around the triazole scaffold, interesting compounds were obtained. We have thus identified receptor antagonists which exhibit sufficient microsomal stability and satisfactory membrane permeability to consider in vivo studies.