Authors
Q. WANG (1), E. DELOOSE (2), L. VANCLEEF (1), E. CANOVAI (3), L. CEULEMANS (3), S. STEENSELS (1), R. FARRÉ MARTI (4), J. TACK (2), J. PIRENNE (3), M. LANNOO (5), I. DEPOORTERE (1) / [1] Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium, Gut Peptide Research Lab, [2] Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium, GI motility and sensitivity research group, [3] Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium, University hospital of Leuven, [4] Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium, laboratory of digestion and absorption, [5] Abdominal Surgery, University Hospital of Leuven, , Belgium, University hospital of Leuven
Introduction In health, extra-oral taste receptors on enteroendocrine cells sense nutrients and transmit signals to control the secretion of gut hormones involved in appetite regulation. In disease, disturbances or adaptations in the expression and sensitivity of these receptors may affect metabolism. In obese patients levels of the hunger hormone ghrelin are lower and food fails to suppress plasma ghrelin levels.
Aim
This study aimed to investigate the effect of obesity on 1) the expression of bitter and sweet taste chemosensory signalling pathways in the human gut and 2) on bitter and sweet-induced ghrelin release in ex-vivo gut segments/isolated crypts.
Methods Gastric and small intestinal tissue was collected from lean brain-death organ donors (BMI: 24.5±1.0 kg/m2) (fundus, n=6 and distal duodenum, n=5), and from obese patients (BMI: 41.2±1.1 kg/m2) who underwent sleeve gastrectomy (fundus, n=6) or Roux-en-Y gastric bypass surgery (proximal jejunum, n=7), respectively. Mucosal segments or isolated crypts were incubated for 2 hours in Krebs-Ringer buffer (11mM glucose) with denatonium benzoate (DB) (1-20 mM), phenylthiocarbamide (PTC) (1-10 mM), chloroquine (1-5 mM) or glucose (25-200 mM). Octanoyl ghrelin levels were determined by radioimmunoassay in the tissue culture supernatant and corrected for tissue weight (segments) or ghrelin cell content (crypts). The expression of the bitter taste receptors TAS2R4, TAS2R10, TAS2R3 and TAS2R38, sweet taste receptor subunit TAS1R3, sodium dependent glucose transporter 1 (SGLT1) and the glucose transporter 2 (GLUT2) was demonstrated by real-time PCR.
Results In both lean and obese subjects basal ghrelin release in mucosal segments from the fundus was respectively 6.1 fold and 2.3 fold higher than in the small intestine. In obese patients, basal ghrelin release was 3.3 fold lower in the fundus but not in the small intestine compared to lean subjects. Bitter taste receptors TAS2R4 (DB), TAS2R10 (DB), and TAS2R3 (chloroquine) were expressed in mucosal tissue from the fundus and small intestine, while TAS2R38 (PTC) was only present in the small intestine. Obesity down-regulated the expression of TAS2R4 and TAS2R3 in a region-independent manner. In lean subjects, DB increased ghrelin release in a dose-dependent manner (overall P<0.01) with maximal effects at 5mM in the fundus (20.3±10.5 (basal) vs 35.0±18.0 (DB) pg/mg tissue) and in the small intestine (3.2±1.1 vs 7.7±2.8 pg/mg tissue). In obese subjects, DB was as effective as in lean subjects to increase ghrelin release in the fundus (overall P<0.05) (7.8±4.3 vs 10.5±5.9 pg/mg tissue at 5mM). In contrast, small intestinal mucosal segments from obese patients did not respond to DB. In agreement with the receptor expression, both DB (5 mM) and chloroquine (5 mM) but not PTC (10 mM) increased ghrelin release in isolated crypts from the fundus. Obesity tended to down-regulate the expression of the sweet taste receptor subunit TAS1R3, and up-regulated the expression of SGLT1 (3.5 fold) and GLUT2 (3.8 fold) in the small intestine. Glucose (50 mM) decreased octanoyl ghrelin secretion in the fundus of lean (19.8±9.0 vs 13.2±6.5 pg/mg tissue (P<0.01)) and obese subjects (4.9±2.5 vs 3.2±1.7 pg/mg tissue (P<0.01)) to the same extent. Similar effects were observed in the small intestine.
Conclusions Bitter and sweet tastants have an opposite effect on ghrelin release in the human gut. The expression of bitter and sweet chemosensory signalling pathways in the gut is altered in obese patients. Obesity impairs ghrelin release but does not change the effect of glucose on ghrelin release, although bitter-induced ghrelin release is less effective in the small intestine.
