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The research presented within this thesis has focused on the complex and interrelated gastrointestinal mechanisms involved in the regulation of appetite and energy intake. The suppression of appetite and energy intake is mediated, at least in part, by a number of gastrointestinal factors, including gastric distension, the modulation of gastric emptying, gastrointestinal motility and gastrointestinal peptides, including cholecystokinin ( CCK ), glucagon - like peptide - 1 ( GLP - 1 ), peptide tyrosine - tyrosine ( PYY ) and ghrelin. An understanding of these mechanisms is important to determine the pathophysiology of obesity and to allow the identification of targets for the treatment of obesity. The effects of the fat on gastrointestinal function and appetite are dependent upon the digestion of fat to free fatty acids. Animal studies indicate that the effects of free fatty acids on energy intake are more potent than those of triglycerides. The comparative effects of a free fatty acid and a triglyceride on gastric emptying, appetite and energy intake were assessed in healthy lean male subjects. Free fatty acids slowed gastric emptying, stimulated the secretion of CCK, suppressed hunger, increased fullness and suppressed energy intake more potently than triglyceride ( Chapter 5 ). These observations suggest that small amounts of free fatty acids in the small intestine potently modulate gastrointestinal function and energy intake. We had previously demonstrated that intraduodenal infusion of the free fatty acid, lauric acid ( C12 ) ( at 0.375 kcal / min, 106 mM ), stimulates isolated pyloric pressure waves ( IPPWs ), inhibits antral and duodenal pressure waves ( PWs ), stimulates the release of cholecystokinin ( CCK ) and glucagon- like peptide - 1 ( GLP - 1 ), and suppresses energy intake, and that these effects are much greater than those seen in response to isocaloric decanoic acid ( C10 ) infusion. However, C12 was associated with nausea, confounding interpretation of these results. In order to determine whether the effects we had observed were physiological, or related to nausea, we assessed the effects of a range of doses of C12 ( 0.1 - 0.4 kcal / min ) on the above parameters. Intraduodenal infusion of very small amounts of C12, potently modulate gastrointestinal motility, gut hormone secretion and suppresses energy intake at a subsequent meal in a dose - dependent fashion, in the absence of nausea ( Chapter 6 ). However, as both the load and the concentration of the infusions varied, it was unclear whether these effects were load -, or concentration -, dependent. We, therefore, examined the independent effects of load, and concentration, of C12 on these variables, and demonstrated that the effects of C12 on gastrointestinal motility, gut hormone release and energy intake are dependent upon the load, but not the concentration of C12 administered to the small intestine in humans ( Chapter 7 ). Animal studies have indicated that the effects of nutrients on gastrointestinal function and energy intake are dependent upon the length of small intestine exposed to nutrient. In humans, we demonstrated that the modulation of gastrointestinal motility and gut hormone secretion by small intestinal glucose is dependent upon the length of small intestine exposed to nutrient, specifically, the suppression of antral motility, the release of GLP - 1 and the suppression of plasma ghrelin concentrations is dependent upon greater than 60 cm of the small intestine being exposed to glucose ( Chapter 8 ). The inhibitory action of glucagon - like peptide - 1 ( GLP - 1 ) on gastric emptying GE is likely to be important in mediating its effects on glycaemia, appetite and upper gastrointestinal symptoms. In healthy subjects ( i ) the slowing of solid and liquid gastric emptying by exogenous GLP - 1 is associated with increased retention of both solid and liquid in the distal stomach and, even when administered in a " low " dose can induce " gastroparesis " and ( ii ) the effects of GLP - 1 on postprandial glycaemic and insulinaemic responses are predictable on the basis of its effect on gastric emptying, supporting the concept that gastric emptying is a major target mechanism for the clinical use of incretin mimetics ( Chapter 9 ). The feeding inhibitory effects of GLP - 1 are likely to relate to the increased antral meal retention, as a close relationship has previously been demonstrated between antral area ( and content ) with the perception of fullness and subsequent energy intake. An understanding of the physiological adaptations that occur in obesity is essential to enable the development of successful therapies for this condition. There is increasing evidence that consumption of a high - fat diet is associated with the development of obesity. The precise mechanisms by which this occurs are unclear, however, studies in animals suggest that adaptations in the gastrointestinal mechanisms involved in the regulation of appetite and energy intake occur, and may, therefore, predispose to obesity. In particular, studies have demonstrated that the acute effects of exogenous CCK, a hormone that potently suppresses energy intake, are attenuated following exposure to a high - fat diet in rats. In our study, healthy lean male volunteers were exposed to a high - fat diet for a period of 3 weeks, following which the effects of an intravenous infusion of CCK on gastrointestinal motility and energy intake were evaluated. Fasting concentrations of CCK were greater following the high - fat diet, however, we did not demonstrate any differences in the antropyloroduodenal motility or energy intake response to exogenous CCK following ingestion of either diet, suggesting, that at least in the short - term, in healthy lean male subjects consumption of a high - fat diet does not alter the sensitivity to the effects of CCK on antropyloroduodenal motility and energy intake ( Chapter 10 ). The studies reported in this thesis have provided new insights into the mechanisms by which nutrients present within the gastrointestinal tract modulate gastrointestinal function and energy intake. Future studies in obese subjects will be required to determine whether sensitivity of the gastrointestinal tract to nutrients is modulated in the obese state. / Thesis (Ph.D.)--School of Medicine, 2006.

Multiple gut hormones are involved in the regulation of food intake. Secretin (SCT), a classical gut hormone, is released into the circulation from the duodenal S-cells when acidic chyme enters the duodenum and performs the major functions of delaying gastric emptying, stimulating fluid secretion from pancreas and liver to optimize the digestion process. In recent years, SCT and its receptor (SCTR) have been identified in discrete nuclei of the hypothalamus, including the paraventricular nucleus (PVN) and the arcuate nucleus (Arc). The occurrence of SCT and SCTR in the brain regions that are engaged in regulating body energy homeostasis and the release pattern of SCT after meals support a functional role of SCT in appetite control. In this study, the effect of SCT on feeding behavior was investigated using wild-type (wt), SCT?/?, and SCT receptor-deficient (SCTR?/?) mice. We found that both central and peripheral administration of SCT could reduce food intake in wt but not in SCTR?/?mice. SCT induce Fos expression in the PVN and Arc, suggesting the activation of hypothalamic feeding centers by this peptide. Consistent with this notion, SCT was found to increase proopiomelanocortin (POMC), but reduce agouti-related protein (AgRP) transcripts in the Arc, and augment thyrotropin-releasing hormone (TRH) and melanocortin-4 receptor (MC4R) mRNA expression in the PVN. In addition, pretreatment with SHU9119, an antagonist for MC4R, abolished the anorexia induced by SCT, suggesting that SCT may inhibit food intake via a melanocortin-dependent pathway. Gut hormones signals the brain to modulate the feeding behavior via the vagal afferent nerve, bloodstream or both. Here we showed that peripheral SCT-induced anorexia was attenuated in mice with subdiaphragmatic vagotomy, capsaicin treatment and bilateral midbrain transections. In summary, our data identify peripheral SCT as an anorectic peptide exerting its action via the melanocortin system and the vagal afferent contributes a major route in mediating the inhibitory effect of peripheral SCT on food intake. The present findings advance our understanding of the role of gut hormones in the regulation of appetite. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

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Hypothalamic control of food intake may be overridden by cortical and limbic brain regions that process reward and the hedonic aspect of food, affecting the ability to discriminate between homeostatic and hedonic feeding. Women, in particular may be affected since cognition and perception of reward change during the menstrual cycle. Changes in estrogen and progesterone levels during the menstrual cycle induce changes in appetite and eating behavior. Food intake declines in the peri-ovulatory period when estrogen levels peak, but increases in the luteal phase when progesterone levels increase. In this novel study we introduce a different context in which to study appetite regulation; the menstrual cycle. The two main study objectives were: 1) to compare the BOLD response between the peri-ovulatory and luteal phases of the menstrual cycle and 2) to compare the BOLD response between women in a negative and positive affect state in response to visual food stimuli using functional magnetic resonance imaging. Pictures of food, regardless of their caloric content stimulated greater activation during the follicular phase compared to the luteal phase in the orbitofrontal cortex, fusiform, amygdala and inferior operculum. Activity was present in the hippocampus, ventral tegmental area and nucleus accumbens in response to high calorie images but not low calorie images during the follicular phase. The insula showed selective activity responding to high calorie pictures in the luteal phase and low calorie pictures in the follicular phase. High calorie food cues elicited greater BOLD signal for women reporting negative affect in the putamen, amygdala, pulvinar, prefrontal cortex, pallidum, fusiform and ventral tegmental area. In summary, visual food cues produced a more robust response during the follicular phase of the menstrual cycle and during a negative mood state in brain regions modulating the rewarding and motivational effects of food images. An increased understanding of how appetite-regulating brain regions respond during the menstrual cycle and in different mood states may facilitate the development of new therapies to reduce the incidence of obesity. / Thesis (Master, Physiology) -- Queen's University, 2009-09-25 15:35:15.609

Obesity, through a persistent positive energy and fat balance is of major public health significance due to its detrimental health, social and financial costs. Increasing physical activity levels through recreational exercise and decreasing energy intake have been implicated with obesity prevention. However, the addition of exercise to normally sedentary routines will only prevent positive energy balance if it is not tracked b a compensatory response in energy intake and non-exercise physical activity [also termed non-exercise activity thermogenesis (NEAT)]. The current series of studies set out to examine the quantitative and temporal relationship between exercise and energy balance with specific reference to appetite, energy intake and NEAT. These studies were designed using similar methodologies that could be compared and related to existing studies. The results showed that in younger motivated individuals, moderate-high intensity mandatory exercise increased daily energy expenditure leading to a marked negative energy balance. However for periods of up to two weeks, analysis of temporal trends revealed evidence of compensatory changes to re-establish energy balance (re-equilibrium phase). This re-equilibrium was a result of not only increases in energy intake, but also (and to a greater extent) decreases in NEAT. Inter-individual variability in the extent of compensation was evident and independent of age, sex, BMI and restraint status. Decreases in physical activity did not lead to a compensatory reduction in energy intake and lead to a marked positive energy balance. Using an exercise intervention, in line with government guidelines, in a group venerable to becoming obese showed that body mass was largely unaffected since overall energy expenditure was not significantly elevated, primarily due to a lack of motivation to reach the required exercise prescription. The results have public health significance in the formation of policy to increase physical activity in the population.