The sense of taste informs the body about the quality of ingested foods. Tastant-mediated signals are generated by a rise in free intracellular calcium levels ([Ca(2+)]i) in the taste bud cells and then are transferred to the gustatory area of brain via connections between the gustatory nerves (chorda tympani and glossopharyngeal nerves) and the nucleus of solitary tract in the brain stem. We have recently shown that lingual CD36 contributes to fat preference and early digestive secretions in the mouse. We show here that 1) the induction of an increase in [Ca(2+)]i by linoleic acid is CD36-dependent in taste receptor cells, 2) the spontaneous preference for or conversely conditioned aversion to linoleic acid requires intact gustatory nerves, and 3) the activation of gustatory neurons in the nucleus of the solitary tract elicited by a linoleic acid deposition on the tongue in wild-type mice cannot be reproduced in CD36-null animals. We conclude that the CD36-mediated perception of long-chain fatty acids involves the gustatory pathway, suggesting that the mouse may have a "taste" for fatty foods. This system would constitute a potential physiological advantage under conditions of food scarcity by leading the mouse to select and absorb fatty foods. However, it might also lead to a risk of obesity and associated diseases in a context of constantly abundant food.

BackgroundRecent studies in rodents and humans suggest that the chemoreception of long-chain fatty acids (LCFA) in oral cavity is involved in the spontaneous preference for fatty foods and might contribute to the obesity risk. CD36 and GPR120 are LCFA receptors identified in rodent taste bud cells. The fact that CD36 or GPR120 gene inactivation leads to a decrease in the preference for lipids raises the question of the respective role(s) played by these gustatory lipid-sensor candidates.Methodology/Principal FindingsUsing a combination of biochemical, nutritional and behavioural studies in wild-type, CD36+/−and CD36−/− mice, it was found that: 1°) CD36 and GPR120 display different diurnal rhythms in the gustatory circumvallate papillae, CD36 mRNA levels being down-regulated during the dark period in contrast to GPR120, 2°) this change is due to food intake and strictly dependent of the presence of lipids in the diet, 3°) CD36 protein levels are also rapidly but transiently decreased by the food intake, a two-fold drop in CD36 protein levels being found 1 h after refeeding, followed by a progressive return to the pre-prandial values, 4°) this down-regulation, which has a post-transcriptional origin, seems sufficient to alter the spontaneous fat preference, independently to change in the GPR120 gene expression.Conclusions/SignificanceIn contrast to GPR120, CD36 appears to be a food-sensitive lipid sensor in the gustatory circumvallate papillae. Lipid-mediated change in lingual CD36 expression might modulate the motivation for fat during a meal, initially high and then gradually decreasing secondary to the food intake. This short-term lipid-mediated effect is reminiscent of sensory-specific satiety. These findings, which highlight the role played by CD36 in the oro-sensory perception of dietary lipids, raise the possibility of novel pharmacological strategies to modify attraction for fatty foods and decrease obesity risks.

Continuous taste bud cell renewal is essential to maintain taste function in adults; however, the molecular mechanisms that regulate taste cell turnover are unknown. Using inducible Cre-lox technology, we show that activation of β-catenin signaling in multipotent lingual epithelial progenitors outside of taste buds diverts daughter cells from a general epithelial to a taste bud fate. Moreover, while taste buds comprise 3 morphological types, β-catenin activation drives overproduction of primarily glial-like Type I taste cells in both anterior fungiform (FF) and posterior circumvallate (CV) taste buds, with a small increase in Type II receptor cells for sweet, bitter and umami, but does not alter Type III sour detector cells. Beta-catenin activation in post-mitotic taste bud precursors likewise regulates cell differentiation; forced activation of β-catenin in these Shh+ cells promotes Type I cell fate in both FF and CV taste buds, but likely does so non-cell autonomously. Our data are consistent with a model where β-catenin signaling levels within lingual epithelial progenitors dictate cell fate prior to or during entry of new cells into taste buds; high signaling induces Type I cells, intermediate levels drive Type II cell differentiation, while low levels may drive differentiation of Type III cells.

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.

Wnt/β-catenin signaling initiates taste papilla development in mouse embryos, however, its involvement in taste cell turnover in adult mice has not been explored. Here we used the BATGAL reporter mouse model, which carries an engineered allele in which the LacZ gene is expressed in the presence of activated β-catenin, to determine the responsiveness of adult taste bud cells to canonical Wnt signaling. Double immunostaining with markers of differentiated taste cells revealed that a subset of type I, II and III taste cells express β-galactosidase. Using in situ hybridization, we showed that β-catenin activates the transcription of the LacZ gene mainly in intragemmal basal cells that are immature taste cells, identified by their expression of Sonic Hedgehog (Shh). Finally, we showed that β-catenin activity is significantly reduced in taste buds of 25 week-old mice compared to 10 week-old animals. Our data suggest that Wnt/β-catenin signaling may influence taste cell turnover by regulating cell differentiation. Reduced canonical Wnt signaling in older mice could explain in part the loss of taste sensitivity with aging, implicating a possible deficiency in the rate of taste cell renewal. More investigations are now necessary to understand if and how Wnt signaling regulates adult taste cell turnover.

Taste stimuli are transduced by taste buds and transmitted to the brain via afferent gustatory fibers. Renewal of taste receptor cells from actively dividing progenitors is finely tuned to maintain taste sensitivity throughout life. We show that conditional β-catenin deletion in mouse taste progenitors leads to rapid depletion of progenitors and Shh+ precursors, which in turn causes taste bud loss, followed by loss of gustatory nerve fibers. In addition, our data suggest LEF1, TCF7 and Wnt3 are involved in a Wnt pathway regulatory feedback loop that controls taste cell renewal in the circumvallate papilla epithelium. Unexpectedly, taste bud decline is greater in the anterior tongue and palate than in the posterior tongue. Mutant mice with this regional pattern of taste bud loss were unable to discern sweet at any concentration, but could distinguish bitter stimuli, albeit with reduced sensitivity. Our findings are consistent with published reports wherein anterior taste buds have higher sweet sensitivity while posterior taste buds are better tuned to bitter, and suggest β-catenin plays a greater role in renewal of anterior versus posterior taste buds.

Obesity is recognized as a worldwide health problem. Overconsumption of fatty foods contributes significantly to this phenomenon. Rodents, like humans, display preferences for lipid-rich foods. Rodents thus provide useful models to explore the mechanisms responsible for this complex feeding behavior resulting from the integration of multiple oral and postoral signals. Over the last decades, the lipid-mediated regulation of food intake has received considerable attention. By contrast, orosensory lipid perception was long thought to involve only textural and olfactory cues. Recent findings have challenged this limited viewpoint. These recent data strongly suggest that the sense of taste also plays significant roles in the spontaneous preference for fatty foods. This paper provides a brief overview of postoral regulation of food intake by lipids and then highlights recent data suggesting the existence of a "fatty taste" which might contribute to lipid overeating and hence to the risk of obesity.

Embryonic taste bud primordia are specified as taste placodes on the tongue surface and differentiate into the first taste receptor cells (TRCs) at birth. Throughout adult life, TRCs are continually regenerated from epithelial progenitors. Sonic hedgehog (SHH) signaling regulates TRC development and renewal, repressing taste fate embryonically, but promoting TRC differentiation in adults. Here, using mouse models, we show TRC renewal initiates at birth and coincides with onset of SHHs pro-taste function. Using transcriptional profiling to explore molecular regulators of renewal, we identified Foxa1 and Foxa2 as potential SHH target genes in lingual progenitors at birth, and show SHH overexpression in vivo alters FoxA1 and FoxA2 expression relevant to taste buds. We further bioinformatically identify genes relevant to cell adhesion and cell locomotion likely regulated by FOXA1;FOXA2, and show expression of these candidates is also altered by forced SHH expression. We present a new model where SHH promotes TRC differentiation by regulating changes in epithelial cell adhesion and migration.