Denatonium induces secretion of glucagon-like peptide-1 through activation of bitter taste receptor pathways

Abstract

Aims/hypothesis This study was designed to ascertain whether human enteroendocrine cells express bitter taste receptors, and whether activation of these receptors with bitter-tasting ligands induces secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Methods We used human enteroendocrine NCI-H716 cells, isolated duodenal segments from mice, and whole mice as our experimental systems for investigating stimuli and mechanisms underlying GLP-1- and PYY-stimulated release. We measured hormone levels by ELISA and determined bitter taste receptor expression by real-time quantitative PCR. We adopted a pharmacological approach using inhibitors and enhancers of downstream signalling pathways known to be involved in bitter taste transduction in taste bud cells to investigate these pathways in NCI-H716 cells. Results Using a pharmacological approach, we identified signalling pathways triggered by the denatonium benzoate (DB)-activated bitter receptors. This involved activation of α-gustducin (Gαgust)—the specific G-protein subunit that is also present in taste bud cells—reduction of intracellular cAMP levels and enhancement of phospholipase C (PLC) activity, which ultimately led to increased intracellular calcium concentrations and hormone release. Gavage of DB, followed by gavage of glucose, to db/db mice stimulated GLP-1 and subsequent insulin secretion, leading to lower blood glucose levels. Conclusions/interpretation Our study demonstrates that activation of gut-expressed bitter taste receptors stimulates GLP-1 secretion in a PLC-dependent manner. In diabetic mice, DB (a ligand of bitter taste receptor cells), when given via gavage, lowers blood glucose levels in diabetic mice after oral glucose administration, through increased secretion of GLP-1.

Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers

“…After administration of DB, this association between motilin 314 plasma levels and antral motility was reduced, but also the positive relationship between 315 motilin plasma levels and hunger scores, confirming our recently published observation that 316 motilin signals hunger (20). 317 It has already been described that taste receptors are expressed on enteroendocrine cells, 318 allowing them to modulate the release of several gastrointestinal hormones (11,12,(39)(40)(41). 319 In mice, intragastric administration of DB (10 mM) significantly increased both total and 320 octanoylated ghrelin levels during the first 30 min after gavage (10).…”

“…Direct 40 intraluminal administration of DB in mice has shown to inhibit ongoing ingestive behavior, to 41 suppress food intake and to inhibit gastric emptying (9,10). Moreover, DB stimulated the in 42 vitro release of glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), which are known 43 to increase satiety and satiation respectively (11,12). Intragastric administration of DB in 44 humans has been shown to impair relaxation of the proximal stomach after infusion of a liquid 45 meal and to increase satiation during an oral nutrient tolerance test (13).…”

“…al. (11) showed that administration of DB in mice increased the secretion of GLP-1, a 344 gastrointestinal hormone known to decrease food intake. Moreover it has been reported that Figure 1.…”

Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells

“…Humans express approximately 25 TAS2 receptors, of which five TAS2Rs, TAS2Rs 7, 10, 14, 43, and 46, can be activated by caffeine (12). In addition to the mouth, TAS2Rs have also been identified in nongustatory tissues, including airway epithelia (13), brain (14), intestinal cells (15,16), and the gastric epithelia of rats and mice (17,18). Beyond their chemosensory function, extraoral TAS2Rs are involved in nonsensory processes to expel or neutralize toxins in the upper and lower airways as well as in the gastrointestinal tract (19).…”

“…Beyond their chemosensory function, extraoral TAS2Rs are involved in nonsensory processes to expel or neutralize toxins in the upper and lower airways as well as in the gastrointestinal tract (19). Furthermore, the TAS2R pathway in the gut is involved in the regulation of food intake, digestion, and satiation (15,16,20,21). Whereas, in the stomach, the endocrine effect of bitter substances on ghrelin secretion has been well described (20), a bitter compound-mediated exocrine function on acid production in parietal cells had not yet been discovered to our knowledge.…”