Bert Avau

Ghrelin signaling in the gut, its physiological properties, and therapeutic potential.

Ghrelin, an orexigenic hormone secreted from the stomach, was soon after its discovery hypothesized to be a prokinetic agent, due to its homology to motilin. Studies in animals and humans, using ghrelin and ghrelin receptor agonists, confirmed this hypothesis, suggesting a therapeutic potential for the ghrelin receptor in the treatment of gastrointestinal motility disorders. Precilinical studies demonstrated that ghrelin can act directly on ghrelin receptors on the enteric nervous system, but the predominant route of action under physiological circumstances is signaling via the vagus nerve in the upper gastrointestinal tract and the pelvic nerves in the colon. Different pharmaceutical companies have designed stable ghrelin mimetics that revealed promising results in trials for the treatment of diabetic gastroparesis and post‐operative ileus. Nevertheless, no drug was able to reach the market so far, facing problems proving superiority over placebo treatment in larger trials.

Targeting extra-oral bitter taste receptors modulates gastrointestinal motility with effects on satiation.

Bitter taste receptors (TAS2Rs) are present in extra-oral tissues, including gut endocrine cells. This study explored the presence and mechanism of action of TAS2R agonists on gut smooth muscle in vitro and investigated functional effects of intra-gastric administration of TAS2R agonists on gastric motility and satiation. TAS2Rs and taste signalling elements were expressed in smooth muscle tissue along the mouse gut and in human gastric smooth muscle cells (hGSMC). Bitter tastants induced concentration and region-dependent contractility changes in mouse intestinal muscle strips. Contractions induced by denatonium benzoate (DB) in gastric fundus were mediated via increases in intracellular Ca2+ release and extracellular Ca2+-influx, partially masked by a hyperpolarizing K+-efflux. Intra-gastric administration of DB in mice induced a TAS2R-dependent delay in gastric emptying. In hGSMC, bitter compounds evoked Ca2+-rises and increased ERK-phosphorylation. Healthy volunteers showed an impaired fundic relaxation in response to nutrient infusion and a decreased nutrient volume tolerance and increased satiation during an oral nutrient challenge test after intra-gastric DB administration. These findings suggest a potential role for intestinal TAS2Rs as therapeutic targets to alter gastrointestinal motility and hence to interfere with hunger signalling.

The bitter truth about bitter taste receptors: beyond sensing bitter in the oral cavity.

The bitter taste receptor (TAS2R)‐family of G‐protein‐coupled receptors has been identified on the tongue as detectors of bitter taste over a decade ago. In the last few years, they have been discovered in an ever growing number of extra‐oral tissues, including the airways, the gut, the brain and even the testis. In tissues that contact the exterior, protective functions for TAS2Rs have been proposed, in analogy to their function on the tongue as toxicity detector. However, TAS2Rs have also been found in internal organs, suggesting other roles for these receptors, perhaps involving as yet unidentified endogenous ligands. The current review gives an overview of the different proposed functions for TAS2Rs in tissues other than the oral cavity; from appetite regulation to the treatment of asthma, regulation of gastrointestinal motility and control of airway innate immunity.

The Gustatory Signaling Pathway and Bitter Taste Receptors Affect the Development of Obesity and Adipocyte Metabolism in Mice

Intestinal chemosensory signaling pathways involving the gustatory G-protein, gustducin, and bitter taste receptors (TAS2R) have been implicated in gut hormone release. Alterations in gut hormone profiles may contribute to the success of bariatric surgery. This study investigated the involvement of the gustatory signaling pathway in the development of diet-induced obesity and the therapeutic potential of targeting TAS2Rs to induce body weight loss. α-gustducin-deficient (α-gust-/-) mice became less obese than wild type (WT) mice when fed a high-fat diet (HFD). White adipose tissue (WAT) mass was lower in α-gust-/- mice due to increased heat production as a result of increases in brown adipose tissue (BAT) thermogenic activity, involving increased protein expression of uncoupling protein 1. Intra-gastric treatment of obese WT and α-gust-/- mice with the bitter agonists denatonium benzoate (DB) or quinine (Q) during 4 weeks resulted in an α-gustducin-dependent decrease in body weight gain associated with a decrease in food intake (DB), but not involving major changes in gut peptide release. Both WAT and 3T3-F442A pre-adipocytes express TAS2Rs. Treatment of pre-adipocytes with DB or Q decreased differentiation into mature adipocytes. In conclusion, interfering with the gustatory signaling pathway protects against the development of HFD-induced obesity presumably through promoting BAT activity. Intra-gastric bitter treatment inhibits weight gain, possibly by directly affecting adipocyte metabolism.

Ghrelin is involved in the paracrine communication between neurons and glial cells.

Ghrelin is the only known peripherally active orexigenic hormone produced by the stomach that activates vagal afferents to stimulate food intake and to accelerate gastric emptying. Vagal sensory neurons within the nodose ganglia are surrounded by glial cells, which are able to receive and transmit chemical signals. We aimed to investigate whether ghrelin activates or influences the interaction between both types of cells. The effect of ghrelin was compared with that of leptin and cholecystokinin (CCK).

The role of nutrient sensing in the metabolic changes after gastric bypass surgery

Taste receptors coupled to the gustatory G-protein, gustducin, on enteroendocrine cells sense nutrients to regulate gut hormone release. During Roux-en-Y gastric bypass (RYGB) surgery, the altered nutrient flow to more distal regions can affect gustducin-mediated gut hormone release and hence energy and glucose homeostasis. We studied the role of gustducin-mediated signaling in the metabolic improvements and intestinal adaptations along the gut after RYGB surgery in wild-type (WT) and α-gustducin-/- (α-gust-/-) mice. RYGB surgery decreased body weight in WT and α-gust-/- mice, whereas food intake was only decreased in WT mice. Pair-feeding to the RYGB group improved glucose homeostasis to a similar extent in WT mice. GLP1 levels were increased in both genotypes, PYY levels in α-gust-/- mice and octanoyl ghrelin levels were not affected after RYGB surgery. In WT mice, nutrients act via α-gustducin to increase L-cell differentiation (foregut) and L-cell number (foregut and hindgut) in a region-dependent manner. In α-gust-/- mice, the effect on gut hormone levels is probably tuned via increased peptide sensor and glucose transporter expression in the Roux limb and increased caecal butyrate and propionate levels in the hindgut that activate free fatty acid receptors. Finally, signaling via α-gustducin plays a role in the increased ion transport of the foregut but not in the improvement in colonic barrier function. In conclusion, RYGB surgery decreased body weight in both WT and α-gust-/- mice. Elevated plasma GLP1 and PYY levels might mediate this effect, although α-gustducin differentially affects several regulatory systems in the foregut and hindgut, tuning gut hormone release.

Supplementation of oligofructose, but not sucralose, decreases high-fat diet induced body weight gain in mice independent of gustducin-mediated gut hormone release

Scope: Enteroendocrine cells sense nutrients through taste receptors similar to those on the tongue. Sweet and fatty acid taste receptors (FFAR) coupled to the gustatory G‐protein, gustducin, on enteroendocrine cells play a role in gut hormone release. We studied if supplementation of artificial (sucralose) or prebiotic (oligofructose; OFS) sweeteners target gustducin‐mediated signaling pathways to alter gut hormone release and reduce obesity‐associated disorders. Methods and results: Wild‐type (WT) and α‐gustducin knockout (α‐gust−/−) mice were fed a high‐fat diet and gavaged once daily (8 wk) with water or equisweet concentrations of sweeteners. OFS but not sucralose decreased body weight gain (−19 ± 3%, p < 0.01), fat pad mass (−55 ± 6%, p < 0.001), and insulin resistance (−39 ± 5%, p < 0.001) independent of α‐gustducin. Neither sweetener improved glucose intolerance, while solely OFS improved the disturbed colonic permeability. OFS decreased (−65 ± 8%, p < 0.001) plasma glucagon‐like peptide 1 (GLP‐1) but not ghrelin and peptide YY (PYY) levels in WT mice. Cecal acetate and butyrate levels were reduced by OFS in both genotypes suggesting enhanced uptake of SCFAs that may target FFAR2 (upregulated expression) in adipose tissue. Conclusion: OFS, but not sucralose, reduced body weight gain and decreased intestinal permeability, but not glucose intolerance. Effects were not mediated by altered gut hormone levels or gustducin‐mediated signaling. Artificial sweeteners do not affect gut hormone levels and are metabolically inert in mice on a high‐fat diet. In contrast, prebiotic oligosaccharides (OFS) prevent body weight gain but not glucose intolerance. Alterations in sweet and short‐chain fatty acid receptors (FFAR) (studied in WT and α‐gust−/− mice) that regulate gut hormone levels are not mandatory for the positive effects of OFS. Enhanced uptake of SCFAs may favor interaction with FFAR2/3 on adipose tissue to induce weight loss.