Small intestinal targets involved in food intake regulation

Background and aim: The worldwide increasing prevalence of overweight and obesity raises concerns for health. There is a clear need for preventive strategies, because current preventative interventions have proven to be unsuccessful in the long term. New strategies may be developed based on targets in the small intestine by activating satiety signals. The thesis aimed to investigate small intestinal targets contributing to food intake regulation. These targets included serotonin, the vagal nerve and the intestinal brake mechanism. Methods: The effects of ileal stimulation with safflower oil (lipid mixture), casein (protein), sucrose (carbohydrate) and rebaudioside A (non-caloric sweetener) on GLP-1 and PYY release were investigated by applying an porcine ex vivo intestinal segment model. The same model was also used to investigate if serotonin is involved in (non-)nutritional-induced GLP-1 and PYY release. The contribution to satiation of GLP-1 and CCK receptors at the vagal nerve, was studied by investigating the effects of GLP-1 and CCK receptor antagonists on ad libitum food intake in a pig model of subdiaphragmatic vagotomy. Two placebo controlled randomized crossover studies were performed in healthy volunteers to investigate the effects of small intestinal macronutrient delivery on ad libitum food intake and satiety signals. The first study compared the effects of duodenal, jejunal and ileal casein delivery on ad libitum food intake and satiety signals. The second study investigated if ileal delivery of all three macronutrients results in activation of satiety signals and reduction in ad libitum food intake. In addition, it was investigated if ileal delivery of native casein is efficiently digested and absorbed and does not result in adverse effects. In both studies the nutrients were delivered to the small intestine by inserting a nasointestinal feeding tube in healthy volunteers. Results: All macronutrients and rebaudioside A stimulated GLP-1 and PYY release from ileal tissue segments. Protein and fat stimulated serotonin release. Inhibiting the reuptake of serotonin resulted in enhanced nutrient induced GLP-1, PYY and CCK release. Serotonin stimulated GLP-1 release from enteroendocrine cells via a serotonin receptor mediated process. Results of the in vivo pig study showed that antagonism of the CCK receptor increased food intake in both vagotomized and sham operated pigs. Blocking the GLP-1 receptor did not affect food intake in both groups. The human studies showed that ileal protein delivery inhibited food intake and activated satiety signals as compared to duodenal or jejunal protein delivery. Also, ileal delivery of small quantities (51.7 kcal) of each macronutrient decreased food intake and activated satiety signals. In addition, it was shown that ileal delivery of native casein resulted in a time and concentration depended increase in plasma concentrations of amino acids and did not result in activation of immune responses nor in gastrointestinal complaints. Conclusions: The data presented in this thesis show that ileal delivery of all macronutrients results in activation of satiety signals and reduction of food intake. Stimulation of the ileum resulted in the strongest activation of satiety signals and inhibition of food intake compared to duodenal and jejunal stimulation. Besides direct nutrient-receptor interaction, the ileum senses (non-)nutritional stimuli via serotonin mediated processes resulting in GLP-1 release. In conclusion, these results demonstrate that targeting the ileum with small amounts of macronutrients is safe and has potential as a weight management strategy.