The role of the gastrointestinal tract in the generation of hunger peaks

The worldwide epidemic of obesity has increased the interest in the mech anisms that regulate hunger and food intake. Several studies have focuse d on the role of the gastrointestinal hormone ghrelin in the pathogenesi s of obesity. Indeed ghrelin is a known orexigenic hormone but also a po werful prokinetic. Exogenous administration of ghrelin is known to induc e a gastric phase III of the MMC. Strong gastric contractions during the fasting state, later identified as gastric phase III contractions of th e MMC, have been implicated in the generation of hunger pangs. Motilin, another gastrointestinal hormone, was identified as the physiological re gulator of gastric MMC activity since a peak of motilin plasma levels pr ecedes phase III contractions that start in the antrum. In addition, exo genous motilin is able to induce gastric phase III activity. The role of ghrelin in the generation of the MMC in humans has however not been elu cidated. Information on the role of the MMC in the generation of hunger feelings in obese patients is lacking. The primary aim of this thesis wa s therefore to study the role of ghrelin in the generation of the MMC an d the role of motilin and/or ghrelin in the generation of hunger in heal thy volunteers and obese patients prior and after RYGB surgery. Already in the beginning of the 20th century it was shown that intragastric admi nistration of bitter receptor tastants was able to inhibit both gastric contractions and hunger feelings. The recent finding that bitter taste r eceptors are also expressed on the endocrine cells of the GIT suggests a possible role for ghrelin and motilin in this inhibition. As a secondar y aim we evaluated the role of both ghrelin and motilin in the inhibitio n of antral motility and hunger during intragastric administration of bi tter receptor agonists.Although ghrelin is able to induce a gastr ic phase III when administered exogenously in humans, we found that, unl ike motilin, ghrelin plasma levels did not fluctuate with the phases of the MMC. The lack of a ghrelin plasma peak prior to the start of a gastr ic phase III contraction indicates that ghrelin is not involved in the g eneration of hunger peaks during the MMC. We found that phase III contra ctions of the MMC were associated with hunger peaks and both could be in duced through the administration of erythromycin, a motilin receptor ago nist, in a cholinergic dependent manner in healthy volunteers. Interesti ngly, in obese patients this association between phase III contractions and hunger peaks was lost. Obese patients showed a switch in the origin of phase III contractions from gastric to duodenal and had significantly lower hunger scores during phase III compared to healthy lean controls. Hunger scores could be increased through the induction of a gastric pha se III contraction by erythromycin administration. We found a positive c orrelation between motilin and BMI and a negative correlation between gh relin and BMI. Although motilin plasma levels were higher in obese patients compared to lean controls, the peak of motilin plasma levels prior t o phase III contractions tended to be absent in obese patients which cou ld explain the switch in origin of phase III. We also measured a decreas e in the plasma levels of motilin after RYGB surgery which suggests that motilin plays an important role in the pathogenesis of obesity but a pr ecise mechanism is lacking at the moment. Further research in patients a fter RYGB surgery showed that erythromycin has lost its ability to induc e phase III contractions in the Roux limb. Although hunger scores during spontaneous phase III contractions were not affected by RYGB surgery, h edonic hunger scores did decrease after surgery. Further research is nee ded to elucidate whether the decrease in plasma motilin levels is mediat ing the decrease in hedonic hunger scores.Finally we evaluated th e effect of intragastric administration of bitter taste receptor agonist s on MMC contractility and hunger scores. The increased sensitivity towa rds bitter tastants in the lingual system in women was matched by an inc reased sensitivity towards bitter in the GIT. Indeed the decrease in hun ger scores and antral motility during phase III was more pronounced afte r intragastric administration of DB in women than in men. Both DB and qu inine were able to abolish the fluctuation of antral motility during the fasting state. The positive relationship between antral motility and th e increase in plasma motilin levels was completely abolished after both DB and quinine administration. Only quinine administration inhibited tot al ghrelin plasma levels. The difference in response between these two b itter agonists could be due to the different bitter taste receptors they activate or the different dosages that were used. To conclude, w e have identified that phase III contractions of the MMC were associated with hunger peaks and this was independent from ghrelin plasma levels b ut depends on a motilin cholinergic-driven mechanism. In obese patients this association was lost due to a switch in the origin of phase III con tractions from the stomach to the duodenum but could be restored via the administration of a motilin receptor agonist. Motilin plasma levels wer e higher in obese patients but decreased after RYGB surgery. Although hu nger scores did not decrease after RYGB surgery, hedonic hunger scores d id. These data suggest an important role of motilin in the pathogenesis of obesity but further research is needed to postulate a precise mechani sm. Furthermore we also confirmed the discrepancy in lingual bitter sens itivity between men and women and showed that this was also present in t he GIT. Further research is needed to evaluate if the decrease in motili n plasma levels causes the inhibition of antral motility or if there is a direct effect of bitter receptor agonists on antral smooth muscle cell activity.nrpages: 181status: publishe