Although the sense of taste is already developed very early in life, the tongue is incomparably affected by external and internal stimuli leading to a need for permanent taste cell renewal throughout life. Taste cells have an average life span of 10 to 14 days [56]. This means that approximately 10% of TBC are renewed in each taste bud every day. A huge variety of factors may contribute to taste bud formation and taste cell fate during adulthood. As early as during pregnancy (10 to 13 weeks), the fetus develops differentiated and innervated taste buds suggesting functionality [56]. It has therefore been proposed that tastants present in the amniotic fluid, which are influenced by the maternal diet, may already prime early taste preferences in the developing fetus and thereby contribute to the development of obesity in later life [57]. The initial taste cells derive from the epithelial placodes and differentiate into functional taste cells after birth [56,58]. Wnt/β-catenin signaling is thought to be the main initiating driver of taste placode development. Sonic hedgehog (Shh) is co-expressed and involved in placode formation and taste cell differentiation at least in fungiform papillae [59,60]. In contrast, circumvallate papillae formation seems to be initiated by the fibroblast growth factor (FGF) pathway [61]. Interestingly, early taste cells derived from embryonic Shh+ precursors are lost 4 months after birth and do not contribute to the life-long taste cell turn over [62]. Instead, renewal of taste cells during adulthood is sustained by a stem cell pool surrounding and/or laying within the basal niche of a taste bud [63]. Thereby, taste buds on the anterior and posterior tongue harbor distinct types of K14+ stem/progenitor cells (K14+/Lgr6+ and K14+/Lgr5+, respectively) [56,63]. The Wnt/β-catenin pathway seems to prompt these progenitor cells to either become Shh expressing cells or non-taste keratinocytes. Shh+ cells are a post-mitotic precursor cell population (also named type IV or basal cells) entering the taste bud and developing into either type of taste cells [64]. Further downstream, specific transcription factors such as Skn1a (or POU class 2 homeobox 3 [POU2F3]) or achaete-scute family BHLH transcription factor 1 (Ascl1) are thought to control which exact cell type is finally developing [65,66]. Shh positive basal cells signal towards the epithelial progenitor pool which express the Shh target genes patched 1 (Ptch1) and GLI family zinc finger 1 (Gli1) in order to promote cell turnover [56,58,59]. In addition, the transcription factor SRY-box transcription factor 2 (SOX2) has been shown to interact with Shh and regulate progenitor differentiation [67]. GLI family zinc finger 3 (Gli3), another target of Shh, is as highly expressed in Lgr5+ stem cells and contribute to their proliferation. Gli3 increases the number of Tas1r3 expressing cells indicating that cell fate decisions already take place in progenitor cells rather than only in mature type IV basal cells [68]. Collectively, specific factors trigger a proper taste cell formation and differentiation at all stages and contribute to cell fate decisions. The level of β-catenin is thought to mediate type IV cell formation and differentiation into type I, II, or III cells [62,69].

The complex taste bud structures and distinct differentiation patterns may be relevant for taste (and food) preferences, eating habits and calorie consumption. Together with this important function in the regulation of food intake, the rapid TBC turn-over suggest their manipulation as a novel strategy in the prevention and treatment of obesity. Indeed, the loss of taste is often seen in relation to weight loss due to decreased appetite [70,71]. Therefore, the following sections summarize current knowledge on the sense of taste in relation to obesity and how obesity may affect adult taste buds.

Over the past decade, the association between body mass index (BMI) and taste perception has been studied extensively with heterogeneous results. It has been repeatedly reported that increased BMI is associated with reduced perceived intensity of different taste qualities and weakened sense of taste [4,6,72,73]. For example, an increasing salty taste threshold (reduced salty sensitivity) was reported to be associated with higher BMI [6]. Other studies reported that adults with obesity perceive sweet and salty taste as less intensive [72] or that women with obesity have an increased mono-sodium-glutamate detection threshold (less sensitive) [73]. However, in the latter study no difference was detected between obese and normal weight women regarding sucrose threshold [73]. Contrasting these data, Hardikar et al. [4] observed a lower sucrose and sodium chloride threshold in obese compared to lean participants and concluded that obese individuals show a higher sensitivity for sweet and salty taste. Further evidence connecting taste sensitivity with obesity is derived from weight loss studies investigating changes in taste after bariatric surgery in rodents and humans. In rodents, preferential behavior is commonly used as a proxy for taste [74]. It is assumed that brief access exposure (10 to 20 seconds) better reflects sensory response to stimuli minimizing the impact of possible post-ingestive effects of direct gut-brain interaction [74]. Numerous studies found a decrease in (high concentrated) sweet taste preference after Roux-en-Y gastric bypass (RYGB) [7,75,76], while no change was observed in response to other stimuli (salt, sour, bitter) [75]. An observed decreased preference for highest concentration of sucrose, but not for the lowest concentration of sucrose was interpreted as postsurgical lower sensitivity to sucrose compared to sham treated controls [7]. Moreover, rats exhibited a strong and persistent aversion to sweet tasting solutions after jejuno-ileal bypass compared to sham-operated rats. This effect could be attenuated by pre-surgery exposure to sucrose [77]. Importantly, observed sweet aversion diminished after reversal of the surgical procedure which was interpreted as an inducible change in taste perception. RYGB and vertical sleeve gastrectomy led to a similar high-sucrose aversion suggesting that sweet taste alterations are not regulated by alterations of the upper gastrointestinal tract [78]. However, opposite effects of RYGB on appetite and responsiveness to sucrose have also been reported [79,80]. Perceived changes in taste after bariatric surgery have also been investigated in humans, using subjective questionnaires as well as more objective controlled and standardized taste studies. Most studies report a perceived increase in sweet taste post-surgically, while some also found patients reporting an increased sensitivity to other taste qualities including salt, sour and bitter taste [81]. Increased sensitivity to sweet, sour and salty taste in some participants was reported after RYGB as well as vertical sleeve gastrectomy, although these appear to be more common in RYGB [82,83]. Beyond that, multiple studies demonstrate an association between the amount of weight loss and taste changes outlined above and even conclude that taste changes post-surgically may be exacerbated by weight loss suggesting a causal relationship between weight and taste perception [83,84]. Studies employing standardized measures to detect taste threshold largely support a post-surgical increase in sweet taste sensitivity, hence a reduced threshold for sweet taste [85,86,87]. Such taste desensitization may subsequently contribute to reduced intake of sweet and energy dense foods. Data reporting lower sweet taste sensitivity after bariatric surgery further suggest large intra-individual differences how weight loss and the bariatric surgery intervention may affect taste and food preferences [5,73]. Similar to the observations for sweet taste, a number of studies point towards a decreased threshold for bitter taste [86,88] while others were not able to demonstrate any change of this taste quality upon weight loss [85]. Few studies reported a decreased threshold for sour taste [87,88], increased sensitivity to umami taste [87], increased sensitivity to salty taste [87] and a decrease in fat taste sensitivity [89]. In line with the aforementioned, sweet taste threshold was shown to decrease (increasing sensitivity) with gradual weight loss in the context of a conservative weight loss program in obese women [90].

Taken together, associations between body weight regulation and changes in taste seem to exist and may underlie the heterogeneous response to weight loss interventions. However, it cannot be ruled out, that other factors than weight loss per se, such as reward value and gut-brain-interaction, drive the observed changes in taste perception. Beyond that, the nature of these described changes in taste perception as well as their association with food intake remains somewhat ambiguous. Although most studies point towards reduced taste sensitivity in obesity, which however is reversible with weight loss, some studies report opposing results [4,6,72,73]. It appears that changes in taste perception effect food selection and food intake [89]. In this sense it is interesting to mention that people with obesity often exhibit an eating behavior characterized by bigger meal sizes, increased snacking behavior and score higher on disinhibition as well as restraint scores which comprise major factors of eating behavior [91,92]. Interestingly, several studies focusing on the genetic background of obesity, eating behavior and food preferences identified genes which play a role in taste sensation. Therefore, the following section will briefly highlight what is known about genetics of eating behavior and food preferences in the context of taste sensation.

In twin studies, the heritability for liking/disliking as well as the preference for a certain food over others has been reported in both, children and adolescents [93]. For instance, mothers of 4 to 5-year-old twins were given a food-questionnaire of 95 foods which were finally grouped into four groups of vegetables, fruits, desserts and meat and fish. For these food groups, lowest heritability estimates were observed for desserts (0.20), moderate for vegetables (0.37) and fruits (0.51) and highest for meat and fish (0.78) [94]. Another study shows that genetic effects on the liking of foods in children may be more related to foods with lower nutrient density such as vegetables (54%), fruits (53%), or proteins (48%) than for snacks (29%), starches (32%), or diary (27%). Interestingly, the opposite was found for environmental factors which seem to have a greater effect on liking of energy dense foods (snacks 60%, starches 57%, and diary 54%) [95]. One study showed high genetic heritability scores for the liking of a sucrose solution with 41% [96]. In addition, the frequency of consumption for high caloric sweets (for example, ice cream, sweets, sweet pastry, chocolate) as well as craving for sweets display high heritability scores (40% and 31%, respectively) suggesting that especially the preference for sweets is strongly genetically determined [96]. This may not be surprising as it ensures sufficient nutrient load and therefore represent an evolutionary survival advantage. Mechanistically, genetic variability of food preferences may be explained by differences in taste perception. Indeed, several studies show genetic variations, such as single nucleotide polymorphisms (SNPs) to be related to the sensation of taste or smell [97,98,99].

For example, SNPs within T1R1 and T1R3, which encode for sweet and umami receptors, have been associated with the loss of monosodium glutamate taste [100]. Most prominently, a common haplotype of the TAS2R38 is critical for the sensitivity to taste 6-n-propylthiouracil (PROP), a component for the taste of bitterness. In own studies, we could show that subjects carrying the PROP-sensitive haplotype consume less coffee and cigarettes compared to those with a different genotype [101]. Women carrying the PROP-insensitive haplotype display higher BMI and waist circumference and have been categorized by a lower restraint level [102]. In another cohort, this “non-taster haplotype” has been associated with higher disinhibition scores in women [99]. Beside these studies connecting sensitivity for tasting bitter components to eating behavior, further evidence shows specific food preferences being related to the genotype of several bitter taste receptors [103]. Interestingly, the sensation of caffeine bitterness was directly associated with messenger ribonucleic acid (mRNA) levels of several T2Rs in human taste papillae and caffeine intake in humans [104]. Therefore, gene-environment interactions seem to be an important mediator for food preference, consumption and caloric intake. Food preferences are mediated very early in life by diverse nutrients challenging the taste system [105]. CD36, a membrane transporter is an important gustatory lipid sensor which also facilitates digestion and further feeds back satiety to the brain [49]. Importantly, a SNP within CD36 is associated with the preferential consumption of oily and lipid-rich foods along with changes in gene expression level of CD36 [49]. Despite CD36, also GPR120 has been identified as lipid receptor in circumvallate taste papillae [48]. Martin and colleagues showed that mRNA expression of CD36, but not GPR120, is directly mediated by dietary fat intake and translated into spontaneous fat preference [48]. Another study could show that linoleic acid induced intracellular Ca²⁺ level of TBC by activating CD36 and GPR120 whereby the latter was only activated by high concentrations of this fatty acid [106]. Moreover, this activation seems to feedback resulting in downregulation of CD36 and upregulation of GPR120. Indeed, TBC from obese mice showed lower Ca²⁺ response to fatty acids [106]. Numerous other SNPs within taste receptor genes have been correlated to taste perception and food preferences and are summarized by Dioszegi et al. [103]. Collectively, these studies demonstrate that nutrients seem to partially drive the transcriptional machinery in taste cells with consequences on food intake. In addition, epigenetic mechanisms may mediate interactions between genetic variations and taste receptor expression. However, mechanistic studies on how genetic variants interact with environmental factors and food intake are scarce.

Despite SNPs in genes functionally related to taste buds, also genetic variations in other genes have been shown to affect the taste perception and are likewise correlated with parameters of obesity. This includes genes which have long been known as obesity candidate markers identified by genome wide association studies (GWASs) including fat mass and obesity (FTO) associated gene or brain derived neurotrophic factor (BDNF) gene. For instance, the variant rs9939609 in FTO is related to dietary fat intake and variants in BDNF are related to increased BMI [107,108,109]. Interestingly, BDNF is also a very important factor in taste bud maintenance as it is crucial to connect new taste cells with afferent nerve fibers [110]. Thereby, BDNF was shown to derive directly from taste cells rather than from the circulation [110]. In this context, it is interesting that variants in BDNF have been linked to altered eating behavior and dietary intake [111,112]. Furthermore, the common missense variant rs6265 previously associated with obesity, was also found in a GWAS for habitual coffee consumption, suggesting a relevance in taste perception [113]. Genetic variations in semaphorin 3 (SEMA3) are associated with obesity as this guidance molecule is relevant in building hypothalamic melanocortin circuits being important for energy homeostasis [114]. In taste cells, SEMA3 is expressed in newly generated bitter taste cells and crucial for mediating a labeled-line connection to appropriate afferent bitter neurons [54]. These findings highlight the importance of oral taste tissue in explaining parts of the missing heritability of obesity. Genetic variations within FGF21 gene, a hormone primarily secreted by the liver, and its co-receptor β-klotho (KLB) are associated with food intake and alcohol consumption [115,116]. Moreover, FGF21 serum concentrations are strongly mediating effects on the consumption of sugar and ethanol [116,117]. Mice with high Fgf21 levels display reduced sugar intake when given the free choice between a regular diet and a diet enriched in sucrose compared to those with lower circulating Fgf21 [116]. These data suggest that already the taste of these diets at the level of lingual papillae might be influenced by serum FGF21 level. Indeed, several studies point out this kind of scenario where homeostatic modulators such as leptin, ghrelin or tumor necrosis factor α (TNF-α) affect the taste sensation by directly targeting the taste tissue [10,118,119]. Therefore, the following paragraph attempts to integrate findings regarding hormonal/inflammatory and epigenetic factors influencing taste bud homeostasis and how obesity-specific changes may impact food selection, further pointing out possible associations with eating behavior.

Hormones can modulate the sense of taste. Strongest support for this notion has been obtained for the adipokine leptin. Leptin acts via binding to its receptor obese receptor (Ob-R) in type II TBC and interferes with local K_ATP channels [10,122]. The activation of K_ATP channel results in reduced sweet response signaling to the afferent nerve fiber in the taste cell and dampens sweet perception [10]. Circadian variations in leptin concentrations are thereby overlay with variations for the sense of sweet [123]. Subjects needed higher concentrations of sucrose and saccharin when they were tested in the evening, when leptin levels peak, compared to the morning, when leptin levels decrease [123]. This diurnal variation was only evident for sweet taste and was not observed in thresholds for other taste stimuli (salty, bitter, sour). Moreover, a phase shift of the diurnal variation of leptin was performed by varying the number of meals leading to significant time-dependent changes in leptin levels which was associated with a parallel phase shift in sweet taste threshold [123]. Circulating leptin levels directly correlate with BMI [124]. As leptin dampens sweet taste sensitivity, it may account for an increased sweet taste threshold (decreased taste sensitivity) often observed in people with obesity [125,126,127]. On the other hand, increased sensitivity to sweet taste in obesity has also been found [128]. This raises the question whether leptin resistance may be of relevance in TBC regulation. In neurons signaling hunger and satiety, leptin resistance can occur as a consequence of obesity [129].

It is of note, that taste receptors have been found in the brain and play a fundamental role in regulating energy metabolism [130]. Highest expression levels have been demonstrated for T1R3, T1R2, T2R116. More interestingly, a decreased expression in obese ob/ob mice and diet induced obese mice compared to a lean control group as well as significant changes after fasting has been reported for these factors. Moreover, leptin but also glucose had an effect on gene expression level of sweet taste receptors in murine hypothalamic neuron derived cells. These results indicate that taste receptors in the brain are involved in recognizing and sensing energy status and might be implicated in the control of energy homeostasis. It was further concluded that these extra-oral taste receptors may contribute to obesity and are modulated by endocrine factors [130].

More recently, adiponectin, has been supposed to be relevant in TBC which express all types of adiponectin receptors [131]. Although adiponectin knock-out mice show no differences in licking behavior by presenting a lipid emulsion, overexpression of salivary adiponectin in these mice resulted in increased responses [131]. This suggests that local adiponectin secretion is more relevant than systemic levels. Local adiponectin might derive from the salivary glands [121]. However, obese people often show elevated tongue fat which, might be a local source of adipokines affecting taste signaling [132].

However, TBC themselves have an endocrine function. Like it is known in extra-oral tissues, taste receptors can be understood as a sort of sensor for environmental factors and are involved in regulating hormone production or secretion. For example, the thyroid hormones triiodothyronine and thyroxine are released through thyroid stimulating hormone dependent Ca²⁺ signaling [133]. This was influenced by bitter compounds which are recognized by Tas2Rs in the thyroid gland [133]. Tas1Rs in β-cells are implicated in insulin secretion and therefore also mediating the homeostatic response to food intake. In entero-endocrine cells they regulate the release of glucagon like peptide-1 (GLP-1). Therefore, hormonal influence on taste cells may regulate taste signaling, but taste receptors seem to regulate local hormone release which indicates a fine-tuning mechanism for dietary feedback.

In mouse taste buds, GLP-1 enhances the response to sucrose and reduces the taste of sour [134]. Moreover, GLP-1 is released into the blood in response to lingual sugar supply during the cephalic phase response [135]. The release of GLP-1 from taste cells was also shown to be mediated by the binding of LCFAs to the lipid receptor GPR120 which is a mechanism for the secretion of GLP-1 in L-cells [134]. On the other hand, LCFAs are known to downregulate mRNA level of CD36 in taste cells; however, GLP-1 secretion is independent of this receptor [20]. Overall, GLP-1 signaling in TBC does not only affect taste sensation, but triggers the activity of this hormone during the cephalic phase and therefore mediates satiety signals.

Ghrelin, an appetite stimulating hormone derived from the stomach, has been found to be expressed in all types of TBC together with its receptor growth hormone secretagogue receptor (GSHR) [119] and the ghrelin O-acetyltransferase (GOAT) necessary for post-transcriptionally active ghrelin. Specific knock-out of these components in mice resulted in altered responses to salty and sour food stimuli [119,136]. Moreover, GOAT knock-out animals exhibit lower consumption of sweet solutions (sucrose and maltodextrin), reduced weight gain and improved glucose and insulin homeostasis [136]. Hence, the acetylation of ghrelin in taste cells might also relate to sweet sensation. At this point, it is interesting to mention that also type 2 diabetes mellitus has been related to dysgeusia and altered taste thresholds [137].

It may therefore not be surprising that important modulators of the glucose homeostasis, including glucagon and insulin, have been proven to be functionally relevant in TBC. Briefly, glucagon together with its receptor is expressed in TBC with highest abundance in T1R3 cells [138]. Not surprisingly, the authors found that glucagon increases the response to sweet stimuli in mice [138]. Insulin mRNA has been found in type II and III cells, and insulin secretion from taste cells has now been confirmed [139]. Like in the gut, insulin is thought to upregulate the expression of ENaC receptors in taste cells. Indeed, lingual administration of insulin increases the response to salty foods. [140]. Recently, Takai et al. [141] treated taste bud organoids in vitro with insulin which resulted in a dose-dependent downregulation of several TBC genes. Moreover, they found a loss of taste cell number in these organoids related to the mechanistic target of rapamycin pathway suggesting that insulin is relevant for taste cell proliferation. With respect to the fact that obesity is linked to the development of insulin resistance and type 2 diabetes mellitus, alterations in gustatory taste perception seems to be a consequence of metabolic disturbances caused by extreme overweight. Due to the high flexible nature of taste cell turnover in adulthood, especially nutritional and hormonal mediators, might be used to alter food preferences and eating behavior by directly targeting the taste cells rather than whole body metabolism.

The relevance of further hormones and signaling peptides involved in energy homeostasis in taste cells has been elegantly summarized by recent reviews [18,20,121,142]. In brief, endocannabinoids, oxytocin, neuropeptide Y (NPY), peptide YY (PYY), cholecystokinin (CCK), vasoactive intestinal peptide (VIP), and galanin may play a role in TBC regulation (Table 1) [10,20,75,119,121,131,134,138,139,140,141,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164].

Extra-oral expression of taste receptors are implicated in innate immunity, inflammatory and autoimmune diseases are associated with altered taste perception, highlighting the potential relevance of taste cell-immune system-crosstalk [142,165]. For example, intranasal taste receptors as well as those found in the respiratory tract, urethra and intestine have been shown to be protective against pathogens [142].

Accumulating evidence also identifies TBC on the tongue as a direct target for inflammatory agents and demonstrates an effect of acute inflammation on taste bud renewal and life span as well as structural integrity [118,166,167,168,169]. Feng et al. [168] demonstrated that TBC express the TNF receptors TNFR1 and TNFR2 and that the level of TNF in taste cells can be induced by inflammatory stimuli. Beyond that, behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine while their responses to sweet, umami, salty, and sour components remained comparable to those of wild-type mice [118]. A potential underlying mechanism was described by Cohn et al. [169] (2010) who demonstrated that acute inflammation following intraperitoneal lipopolysaccharide injection inhibited proliferation of taste progenitor cells as indicated by reduced expression of Ki67 (antigen Ki67), a cell proliferation marker, resulting in a decreased number of new taste cells. Beyond that a shorter average life span of taste buds became evident. In a different study, toll-like receptors (TLRs) and type I and II interferon (IFN) receptors as well as their downstream signaling components were identified in taste tissue [166] The IFN signaling pathway was activated by administration of TLR ligands (lipopolysaccharide and double-stranded RNA polyinosinic:polycytidylic acid) and upregulates the expression of IFN-inducible genes in taste buds. Moreover, systemic administration of IFNs increased apoptosis of TBC in mice [166]. From these results, a potential effect of inflammation on TBC turnover was postulated. However, obesity comprises a state of low-grade systemic inflammation [170,171]. More recently an implication of low grade inflammation in taste bud homeostasis in obesity has been shown. Kaufman et al. [9] (2018) demonstrated, that taste bud renewal is affected by a specific rather than overall immune response in taste epithelium which was linked to obesity. Mice fed a high fat diet showed an increased expression of TNF-α in taste epithelium compared to lean controls [9]. Morphologically, significant reduced taste bud abundance was observed in obese mice while no differences in size or a change in balance between type I, II, and III cells was observed. TNF-α knockout mice were protected against these effects. Obesity-resistant transgenic mice did neither show an increased TNF-α expression nor changes in markers of taste bud renewal [9]. Taken together, these results strongly suggest, that low grade inflammation and TNF-α affect taste bud homeostasis and renewal.

Obesity seems to interfere with taste bud renewal through different mechanisms. Shh plays a crucial role in taste bud development during embryogenesis but also in TBC renewal throughout life. A study from 2019 shows a differential genome wide gene expression pattern of human fungiform taste buds between lean and obese which includes Shh [3]. How obesity might affect this differential gene expression pattern was not elucidated. However, effects on the transcriptional machinery in taste cells by nutrients, hormones or inflammatory factors via potential epigenetic mechanisms might be of high relevance in taste cell turnover during obesity. Indeed, some studies support epigenetic regulation of key genes involved in taste cell turnover. Just recently, Bar and colleagues found, the polycomp repressive complex 1 (PRC1), a chromatin remodeling complex, to prevent ectopic Shh expression in non-taste lingual epithelium in the developing tongue [172]. Moreover, enrichment analyses of genes being downregulated in Prc1 null mice revealed pathways such as epithelial development and cell differentiation as well as tissue development pathways [172]. Nevertheless, this mechanism has not been shown in adult taste tissue. To date, it can only be hypothesized that DNA methylation changes of key genes such as Shh may be a relevant mechanism to control renewal, fate decision and abundancy of taste cells and receptors. In extra-oral tissues such as brain and liver, it was demonstrated that DNA methylation is involved in the regulation of Shh expression [173]. Interestingly, leptin has been linked with Shh gene regulation in extra-oral tissues [174] and moreover, leptin was shown to cause a downregulation of extra-oral t1r2 and t1r3 expression in the brain of mice [130]. Another study demonstrated global DNA methylation changes in tongue carcinoma while common tongue cancer therapies (accompanied by taste aversion and dysgeusia), target Shh [175,176]. Although this is highly speculative at the moment, future studies may focus on molecular mechanism of the observed gene expression differences in taste cells during obesity.