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Gut induced biomarkers of appetite and satiety

Meyer-Gerspach, Anne Christin. Gut induced biomarkers of appetite and satiety. 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10203

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Abstract

Obesity is basically caused by an imbalance between food intake and energy expenditure. It is well documented that the gastrointestinal tract plays a key role in the control of food intake, but the regulatory circuits and their interactions are complex.
Food enters the gastrointestinal tract, which then trigger specific mechanisms that respond to specific components of food. The anatomical bases for the sensing machinery are enteroendocrine cells in the small intestine, which act as neural triggers or as intestinal satiation peptide secreting cells. These cells express chemosensory receptors that respond to luminal stimuli. This thesis addresses specific mechanisms regarding enteroendocrine cells and how nutrient components interact with this machinery to stimulate and regulate the secretion of gut peptides, which play a key role in the regulation of food intake and a wide range of metabolic functions.
In a first set of experiments, we investigated the involvement of two potential targets of peptide release, such as glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY) and cholecystokinin (CCK): i) bile acids (BAs) as possible TGR5 agonists and ii) glucose stimulating the sweet receptor T1R2/T1R3.
To investigate the physiological role of BAs, subjects received intraduodenal infusions of different loads of chenodeoxycholic acid (CDCA, a primary BA in humans) in comparison to sodium-oleate (a potent secretagogue for the peptides mentioned above) or vehicle as a control. Administration of CDCA resulted in a significant increase of both plasma GLP-1 and CCK levels; however, the stimulatory potency was small, if we compare the magnitude of the GLP-1 and CCK responses to other well-known secretagogues such as glucose or fatty acids.
To investigate the physiological role of T1R2/T1R3 in the secretion of intestinal satiation peptides we used lactisole, a T1R2/T1R3 receptor antagonist. Subjects received i) intragastric and intraduodenal infusions of glucose and ii) intragastric and intraduodenal infusions of a liquid mixed meal, both with and without lactisole. Lactisole induced a significant reduction of plasma GLP-1 levels in both, the intragastric and intraduodenal glucose-stimulated parts. However, we observed no effect of lactisole on gastrointestinal peptide secretion in the mixed liquid meal-stimulated parts. The liquid meal consisted beside glucose also of proteins, fats and other complex carbohydrates. The lack of effect of lactisole suggests that these nutrients induced the release of gastrointestinal peptides probably via other receptor mechanisms and thus outweighed the effect of T1R2/T1R3 blockade. These findings indicate that the receptor is not alone responsible for peptide secretion; it is rather a complex interaction between different receptor mechanisms. In addition, we found that the inhibitory effect of lactisole on the secretion of GLP-1 was greater in response to intragastric glucose administration compared to the intraduodenal infusion. These results let assume interaction mechanisms between gastric signals and signals from the small intestine and indicate a relevant contribution of the stomach in the regulation of gastrointestinal peptide secretion.
Indeed, several studies in animals and humans suggest that gastric and intestinal signals interact to elicit optimal satiation and adequate control of eating. In humans, little information is available on the underlying mechanisms of this interaction. In addition, uncertainties exist about the role of both gastric and intestinal parameters, as well as their interaction in the control of satiation in relation to body mass. In a second set of experience, we investigated the reciprocal control between gastric functions and intestinal parameters in the control of appetite in lean as well as in obese persons.
To investigate this potential interaction, lean subjects received either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. We found that infusions of glucose directly into the small intestine elicit only weak effects on appetite and the secretion of GLP-1 and PYY. In contrast, identical amounts of glucose delivered into the stomach markedly suppressed appetite paralleled by significantly greater plasma levels of GLP-1 and PYY. Administration of the mixed liquid meal showed a similar outcome. It seems that an initial more rapid rate of duodenal delivery after intragastric infusions account for the accelerated secretion of GLP-1 and PYY. These findings suggest again a role of the stomach in the control of appetite and indicate interaction mechanisms between gastric emptying rates and the release of intestinal satiation peptides.
In a last series of experiments, we compared gastric emptying, intestinal peptide release and satiation parameters in response to nutrients between normal weight and obese healthy subjects. We found that gastric emptying rates were delayed in obese subjects, possible due to impaired gastric sensory functions. In addition, the increase in post-prandial plasma GLP-1 and PYY levels was reduced and the caloric intake was higher in obese compared to lean subjects. These results document once more the importance of gastric signals in the control of appetite.
Together, chemosensing receptors like T1R2/T1R3 are involved in the secretion of gastrointestinal peptides, however each receptor by itself is probably not alone responsible for peptide release – it is rather a complex interaction between different receptor mechanisms. In addition, complex interactions between different gastrointestinal signals are responsible for the control of eating. The understanding of each of these signals and interaction mechanisms is essential and could constitute a promising therapeutic approach for the treatment of obesity.
Advisors:Handschin, Christoph
Committee Members:Beglinger, Christoph and Langhans, Wolfgang
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Growth & Development (Handschin)
Item Type:Thesis
Thesis no:10203
Bibsysno:Link to catalogue
Number of Pages:115 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:51
Deposited On:16 Jan 2013 15:40

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