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Sweetness is the preferred taste of humans and many animals, likely because sugars are a primary source of energy. In many mammals, sweet compounds are sensed in the tongue by the gustatory organ, the taste buds. Here, a group of taste bud cells expresses a canonical sweet taste receptor, whose activation induces Ca 2+ rise, cell depolarization and ATP release to communicate with afferent gustatory nerves. The discovery of the sweet taste receptor, 20 years ago, was a milestone in the understanding of sweet signal transduction and is described here from a historical perspective. Our review briefly summarizes the major findings of the canonical sweet taste pathway, and then focuses on molecular details, about the related downstream signaling, that are still elusive or have been neglected. In this context, we discuss evidence supporting the existence of an alternative pathway, independent of the sweet taste receptor, to sense sugars and its proposed role in glucose homeostasis. Further, given that sweet taste receptor expression has been reported in many other organs, the physiological role of these extraoral receptors is addressed. Finally, and along these lines, we expand on the multiple direct and indirect effects of sugars on the brain. In summary, the review tries to stimulate a comprehensive understanding of how sweet compounds signal to the brain upon taste bud cells activation, and how this gustatory process is integrated with gastro-intestinal sugar sensing to create a hedonic and metabolic representation of sugars, which finally drives our behavior. Understanding of this is indeed a crucial step in developing new strategies to prevent obesity and associated diseases.

To assess the biological value of environmental stimuli, animals’ sensory systems must accurately decode both the identities and the intensities of these stimuli. While much is known about the mechanism by which sensory neurons detect the identities of stimuli, less is known about the mechanism that controls how sensory neurons respond appropriately to different intensities of stimuli. The ionotropic receptor IR76b has been shown to be expressed in different Drosophila chemosensory neurons for sensing a variety of chemicals. Here, we show that IR76b plays an unexpected role in lowering the sensitivity of Drosophila sweet taste neurons. First, IR76b mutants exhibited clear behavioral responses to sucrose and acetic acid (AA) at concentrations that were too low to trigger observable behavioral responses from WT animals. Second, IR76b is expressed in many sweet neurons on the labellum, and these neurons responded to both sucrose and AA. Removing IR76b from the sweet neurons increased their neuronal responses aswell as animals’ behavioral responses to sucrose and AA. Conversely, overexpressing IR76b in the sweet neurons decreased their neuronal as well as animals’ behavioral responses to sucrose and AA. Last, IR76b’s response-lowering ability has specificity: IR76b mutants and WT showed comparable responses to capsaicin when the mammalian capsaicin receptor VR1 was ectopically expressed in their sweet neurons. Our findings suggest that sensitivity of Drosophila sweet neurons to their endogenous ligands is actively limited by IR76b and uncover a potential molecular target by which contexts can modulate sensitivity of sweet neurons.

Taste sensitivity relates to food preferences and macronutrients intake. The current study investigated whether the neural responses to food odors varied in sensory quality (sweet or non-sweet) and their associations with macronutrient content (high- or low-fat) in young healthy participants varied in sweet taste sensitivity. Thirty-eight participants were assessed for their sensitivity to sucrose solutions using a modified “taste strip” test. They were divided into high sweetness sensitive (HS, n ​= ​15) and low sweetness sensitive (LS, n ​= ​15) groups using the median split approach. Brain responses to four food-related odors (chocolate, peach, peanut, and bread) and one non-food odor (rose) were assessed using functional magnetic resonance imaging (fMRI). Preferences for tastes and macronutrients were measured using a computer-based task. Behavioral results showed that HS group, compared to LS group, had a higher preference for carbohydrate-dominated foods and liking for sweet foods, but a lower liking for protein-dominated foods. The food odors, in comparison to non-food odors, produced greater brain-activations in the gustatory and reward regions. Compared to LS group, the HS group showed a higher level of activation in the frontal inferior operculum in response to sweet vs. savory food odors, and stronger insular activations to high-fat vs. low-fat food odors. In addition, individual sweetness sensitivity was positively associated with activation of the insula in response to chocolate odor, suggesting an overlap of neural responses to food odor with high sugar and fat content. Our findings highlight that high sensitivity to sweetness can be associated with increased preference for carbohydrate-dominated or sweet foods, and elevated brain activations to sweet or high-fat food odors in the areas related to food reward processing. •The influence of sweetness sensitivity and neurobehavioral response to food tastes and macronutrients were studied.•Higher sweetness sensitivity is related to higher sweet food liking and carbohydrate preference.•Higher sweetness sensitivity is associated with stronger operculum and insula activation for sweet and high-fat food odors, respectively.•Higher sweetness sensitivity is related to increased insula activation in response to sweet high-fat food odor.

Variation in ability to detect, recognize, and perceive sweetness may influence food consumption, and eventually chronic nutrition-related conditions such as overweight and obesity. The aim of this study was to investigate the associations between sweet taste function, anthropometry, and dietary intake in adults. Participants’ (n = 60; mean age in years = 26, SD = ±7.8) sweet taste function for a range of sweeteners (glucose, fructose, sucrose, sucralose, erythritol, and Rebaudioside A) was assessed by measuring detection and recognition thresholds and sweetness intensity. Height, weight, and waist circumference were also measured, and participants also completed a Food Frequency Questionnaire. There was large inter-individual variation in detection, recognition and sweetness intensity measures. Pearson’s correlation coefficient revealed no robust correlations between measures of sweet taste function, anthropometry, and dietary intake, with the exception of suprathreshold intensity, which was moderately correlated with total energy intake (r = 0.23–0.40). One-way analysis of variance revealed no significant differences between the most and least sensitive participants in terms of BMI, waist circumference, and dietary intake for all measures of sweet taste function and sweeteners (all p > 0.01). When stratified into BMI categories, there were no significant differences in any measure of sweet taste function between the normal weight and overweight/obese participants (all p > 0.01). Results show that that sweet taste function is not associated with anthropometry and sweetness intensity measures are the most appropriate measure when assessing links between sweet taste and food consumption.

Background Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host. Results We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance. Conclusions Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice. Trial registration Trial registration number NCT03032640 , registered on January 26, 2017. 3ThJTRkvKM2w8o53nrbAga Video abstract

The sweet taste receptor, which was identified approximately 20 years ago, mediates sweet taste recognition in humans and other vertebrates. With the development of genomics, metabonomics, structural biology, evolutionary biology, physiology, and neuroscience, as well as technical advances in these areas, our understanding of this important protein has resulted in substantial progress. This article reviews the structure, function, genetics, and evolution of the sweet taste receptor and offers meaningful insights into this G protein–coupled receptor, which may be helpful guidances for personalized feeding, diet, and medicine. Prospective directions for research on sweet taste receptors have also been proposed.

The phytochemical study of Wisteria sinensis (Sims) DC. (Fabaceae), commonly known as the Chinese Wisteria, led to the isolation of seven oleanane-type glycosides from an aqueous-ethanolic extract of the roots. Among the seven isolated saponins, two have never been reported before: 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-β-D-glucuronopyranosyl-22-O-acetylolean-12-ene-3β,16β,22β,30-tetrol, and 3-O-β-D-xylopyranosyl-(1→2)-β-D-glucuronopyranosylwistariasapogenol A. Based on the close structures between the saponins from W. sinensis, and the glycyrrhizin from licorice, the stimulation of the sweet taste receptor TAS1R2/TAS1R3 by these glycosides was evaluated.

Sweet substances are detected by taste-bud cells upon binding to the sweet-taste receptor, a T1R2/T1R3 heterodimeric G protein-coupled receptor. In addition, experiments with mouse models lacking the sweet-taste receptor or its downstream signaling components led to the proposal of a parallel “alternative pathway” that may serve as metabolic sensor and energy regulator. Indeed, these mice showed residual nerve responses and behavioral attraction to sugars and oligosaccharides but not to artificial sweeteners. In analogy to pancreatic β cells, such alternative mechanism, to sense glucose in sweet-sensitive taste cells, might involve glucose transporters and KATP channels. Their activation may induce depolarization-dependent Ca2+ signals and release of GLP-1, which binds to its receptors on intragemmal nerve fibers. Via unknown neuronal and/or endocrine mechanisms, this pathway may contribute to both, behavioral attraction and/or induction of cephalic-phase insulin release upon oral sweet stimulation. Here, we critically review the evidence for a parallel sweet-sensitive pathway, involved signaling mechanisms, neural processing, interactions with endocrine hormonal mechanisms, and its sensitivity to different stimuli. Finally, we propose its physiological role in detecting the energy content of food and preparing for digestion.

Sweet taste perception, a critical aspect of the initiation of feeding behavior, is primarily regulated by an animal’s internal metabolic state. However, non-metabolic factors, such as motivational and emotional states, can also influence peripheral sensory processing and hence feeding behavior. While mating experience is known to induce motivational and emotional changes, its broader impact on other innate behaviors, such as feeding, remains largely uncharacterized. In this study, we demonstrated that the mating failure of male fruit flies suppressed sweet taste perception via dopamine signaling in specific neural circuitry. Upon repetitive failure in courtship, male flies exhibited a sustained yet reversible decline of sweet taste perception, as measured by the proboscis extension reflex (PER) towards sweet tastants as well as the neuronal activity of sweet-sensing Gr5a + neurons in the proboscis. Mechanistically, we identified a small group of dopaminergic neurons projecting to the subesophageal zone (SEZ) and innervating with Gr5a + neurons as the key modulator. Repetitive sexual failure decreased the activity of these dopaminergic neurons and in turn, suppressed Gr5a + neurons via Dop1R1 and Dop2R receptors. Our findings revealed a critical role for dopaminergic signaling in integrating reproductive experience with appetitive sensory processing, providing new insights into the complex interactions between different innate behaviors and the role of brain’s reward systems in regulating internal motivational and emotional states.

Saccharin is a commonly used artificial sweetener that exhibits both sweetening and sweet inhibition activities. The species‐dependent response towards saccharin and the interaction between saccharin and the sweet taste receptor T1R2/T1R3 remain elusive. In this study we used mismatched chimeras of T1R2 and T1R3 and calcium mobilization functional analysis to reveal a detailed species‐dependent response towards saccharin of human, squirrel monkey, and mouse sweet taste receptors. Our findings, combined with previous results by others, suggest multiple and complex interaction modes between saccharin and the sweet taste receptor, which are helpful guidelines for effective modulation of the sweet taste by sweetener/sweet inhibitors. Saccharin exhibits both sweetening and sweet inhibition activities. Besides the orthosteric binding site in T1R2 for activating the human sweet taste receptor T1R2/T1R3, it appears that there are at least two allosteric inhibitory sites located in T1R2 and T1R3 respectively to inhibit the receptor activity, suggesting multiple and complex interaction modes between saccharin and the heterodimeric sweet taste receptor T1R2/T1R3.