Gastrointestinal signals regulating appetite in humans

Obesity and its associated complications are a significant health problem in industrialized countries. This fact has generated great interest in the role of the gut in the regulation of food intake in the past three decades. Especially after the discoveries of gastrin, secretin and cholecystokinin (CCK), it was generally accepted that digestive processes are mainly regulated by hormones, but it has become apparent that there is a complex interplay between neural and hormonal pathways. Several systems seem to be involved in the regulation of bodyweight; one of them is primarily concerned with short-term regulation of food intake. The control circuits include central and peripheral signals. Much insight has been gained into physiological processes of satiety peptides like CCK, glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) in the past few years. The informations depicting their mechanism of action and potential interactions between different physiological signals involved in the short-term regulation of satiety are still limited in humans. The main interest of this thesis focuses on the further characterization of some of those signals, especially on the investigation in potential interactions between individual satiety factors. The study set-up applied in the projects was standardized and is similar to experimental conditions used in prior studies. Here are some examples: nearly in every study, volunteers received an intraduodenal (ID) perfusion. To investigate a potential interaction between the stomach and the small intestine, a preload was given or the stomach was distended by a balloon for a short period of time before the test meal was offered. After the preload or the distension of the stomach, a standard meal was presented to the subjects, and they were invited to eat and drink as much as they wished for 60 min. During the study subjects scored their subjective feelings for hunger and fullness for the duration of each experiment using a visual analogue scale (VAS) and blood was drawn in regular intervals. The study was finished 60 min after meal start. The stomach has an obvious role in the regulation of eating behavior, but until recently it was still unclear, if and to what extent pure mechanical distension of the fundus and the antrum can influence food intake. Therefore the first project was designed to further understand the role of a) the gastric fundus and b) the gastric antrum in triggering satiation in healthy male volunteers. From previous study results it was anticipated that distension of the distal stomach could play a role in the generation of satiation. In the first part of our study the fundus was distended by a balloon with increasing volumes. When the fundus was distended, no effect on food intake was observed, but a short-lasting effect on feelings of hunger and fullness. Gastric distension only seems to trigger satiety as long as mechanoreceptors in the stomach are stimulated; the short-lasting effect could indicate that the signals are transmitted via afferent nerves to the central nervous system (CNS). The second part of this study was designed to examine the effect of antrum balloon distension on subsequent food intake; in addition, it was of interest to test whether ID fat could intensify the effect of distal gastric distension. Neither gastric distension alone nor in combination with ID fat reduced the subsequent calorie intake; also no effect was observed on feelings of hunger or fullness. ID fat does not seem to intensify gastric satiety signals induced by pure mechanical distension of the stomach. Neither fundus nor antrum distension altered CCK and PYY plasma concentrations. This fact implies that signals induced by pure mechanical gastric distension are not mediated by circulating CCK or PYY. During ID fat perfusion, CCK and PYY plasma concentrations were significantly increased. The increase of CCK after ID fat confirmed previous study results. However, this study was one of the first which could show an increase of PYY after ID fat in humans. Due to these study results pure mechanical gastric distension of the fundus or the antrum is presumably not a sufficient satiety signal to influence subsequent food intake. An interaction effect on food intake resulting from an intestinal and a gastric satiety signal was already explored for CCK, but not for GLP-1. It was therefore of interest to find out whether an interaction exists between a preload and intravenous (i.v.) GLP-1. In the second project GLP-1 was given i.v. in a dose which mimics physiological GLP-1 plasma concentrations; the dose reduced calorie intake confirming previous study results. One major observation of this study was the demonstration that a protein-containing preload together with i.v. GLP-1 enhanced the satiety-inducing effects of GLP-1 compared to a water preload plus infusion of GLP-1. This result provides strong evidence that GLP-1 interacts with gastric signals to modulate food intake and satiety in humans. We inferred that GLP-1 is an important satiety factor which interacts with other satiety signals in order to control food intake and satiety. However, it still remains unclear whether the satiety effects of GLP-1 are directly mediated through peripheral or central receptors or indirectly by releasing other satiety peptides. The following study was designed to further understand the potential interaction between protein and fat in regulating food intake in humans. It is known that ID lipid infusions and protein given as an oral preload reduce food intake in humans and from previous study results we inferred that ID fat interacts with gastric signals to regulate food intake. In the third project we were interested in exploring the potential interaction of the stomach and the small intestine; we also wanted to see whether GLP-1 and PYY are associated with this interaction. ID fat perfusion alone reduced the amount of food eaten and the total calorie intake, but the reduction did not reach statistical significance. Although the design of the present study was similar to previous studies with respect to fat dose, experimental design and duration of fat perfusion, the variability of the individual responses to ID fat was greater than in previous studies and the reduction of food intake did not reach statistical significance. Due to these results it can be speculated that certain individuals have a reduced sensation to ID fat. The effects of ID fat on food intake do not seem to be mediated by changes in plasma GLP-1 or PYY levels, but they are largely dependent on CCK release, which is in agreement with previous findings. When subjects consumed an oral protein preload, calorie intake was significantly reduced. The increase of premeal plasma concentrations of GLP-1 and PYY did not differ compared to placebo. Therefore the inhibitory effect of oral protein on eating behavior is not mediated by changes in circulating plasma hormone levels. The simultaneous administration of an oral protein preload and ID fat did not show a synergistic reduction in calorie consumption, rejecting the hypothesis that oral protein and ID fat exert a positive synergistic effect. The fourth project examined the physiological and the pharmacological role of PYY in regulating eating behavior. Due to human study results it was supposed that PYY (3-36) is a potent physiological regulator of satiety with a potential for therapeutic application. Because the physiological role of PYY in humans has not been investigated in detail, we first wanted to define a range of physiological PYY plasma levels after two meals differing in their calorie content. The results showed that only large meals are able to stimulate the release of larger amounts of PYY, whereas a low-calorie meal has minimal effects on postprandial hormone plasma levels. In the second part of the study we wanted to examine the effects of graded doses of i.v. PYY (3-36) on eating behavior in healthy human subjects. We found a dose-dependent satiety effect of i.v. applied PYY (3-36). These results support the hypothesis that exogenously administrated PYY (3-36) is able to suppress food intake in humans. However, when the postprandial physiological levels of PYY after the high calorie meal are compared to those obtained after peripheral administration, it can be suggested that the significant satiety effect of PYY (3-36) is only seen at plasma concentrations higher than those after a large meal. The smallest administered dose of PYY (3-36) did not significantly reduce food intake and showed PYY plasma levels about in the same range as the physiological ones. Due to these results we infer that the PYY satiety effect seen with the middle and the highest dose of exogenous PYY (3-36) was rather a pharmacological than a physiological effect. It seems to be unlikely that PYY is a major physiological satiety factor, but still more information is necessary. Dose-dependent side effects of PYY (3-36) like nausea and vomiting could be observed. PYY (3-36) seems to have a narrow therapeutic window, which could limit its therapeutic potential. In summary it was shown in the present thesis that 1) pure gastric balloon distension of the fundus and the antrum is not a sufficient satiety signal to influence subsequent food intake; 2) the effect of gastric distension on eating behavior is not amplified by ID fat; 3) GLP-1 is an important satiety factor and seems to interact with gastric signals to modulate food intake and satiety in humans; 4) the satiating effect of protein as an oral preload cannot be amplified by ID fat; 5) the release of physiological PYY is dependent on the calorie content of a meal; 6) exogenous PYY (3-36) reduces food intake in a dose-dependent manner; 7) the effect of exogenous PYY (3-36) on food intake seems to be a pharmacological rather than a physiological effect; 8) PYY (3-36) has a narrow therapeutic window.