Sweet Taste Receptor Research Articles

Activation of a Sweet Taste Receptor by Oleanane-Type Glycosides from Wisteria sinensis.

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.

Red algae-derived isofloridoside activates the sweet taste receptor T1R2/T1R3

Isofloridoside (IF) is a naturally occurring galactosylglycerol compound with a refreshing sweet taste. It is found in red algae, where it acts as a photosynthetic intermediate. However, the mechanism by which IF elicits sweetness has not been determined. In this study, we investigate the interaction between IF and the sweet taste receptor T1R2/T1R3. We show that IF causes an increase in intracellular Ca2+ concentration and an increase in Erk phosphorylation in T1R2/T1R3-expressing HEK293T cells, indicating that IF interacts with T1R2/T1R3. IF also activates endogenously expressed T1R2/T1R3 in mouse small intestinal endocrine L-cells, and promotes the secretion of the incretin glucagon-like peptide-1 (GLP-1). In silico docking simulations of IF and T1R2/T1R3 predict that IF forms hydrogen bonds with Tyr103 in the extracellular Venus flytrap domain of T1R2. This result is consistent with the binding mode of many other sweet-tasting molecules. We found that IF have the potential as a new alternative sweetener.

Genetic variation in sweet taste receptors and a mechanistic perspective on sweet and fat taste sensation in the context of obesity.

Taste sensation enables humans to make nutritionally important decisions such as food preference and consumption. It functions as deterministic factors for unpropitious eating behavior, leading to overweight and obesity. The hedonistic feeling on consumption of fat and sugar-rich meals, in particular, has a negative influence on health. In addition, impairment in the taste receptors alters the downstream signaling of taste transduction pathway. Hence, genetic polymorphism in typical taste receptors is a predictor of taste sensitivity variance across individuals. The present review summarizes the effect of a single nucleotide polymorphism (SNP) in sweet taste receptors (T1R2/T1R3) on taste perception among individuals of various body mass index (BMI). Furthermore, in the context of obesity, we discussed the possibility of crosstalk between fat and sweet receptors as well as taste dysfunction in diseased individuals. In overall, a greater understanding of the physiological relationship between taste receptors, altered taste sensitivity, and genetic polymorphisms should lead to more effective obesity prevention approaches.

Early-life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats.

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region-specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling-related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.

Sweet taste receptors are the potential mediator involved in appetite regulation of grass carp in response to high digestible carbohydrates intake

Glucosensing evokes complex neural and endocrine responses that control glucose utilization in mammals. Until now, the glucosensing mechanism studies in fish have been mostly concentrated in carnivorous fishes and omnivorous fishes, lacking in herbivorous fishes. To lay a better understanding of herbivorous fish glucosensing mechanism, we first established a high digestible carbohydrates (HDC) intake model of grass carp with steadily reduced daily food intake compared with control diet intake. The blood glucose level of the HDC group was significantly higher than the control group within postprandial 2 h, and then no further increasing blood glucose was detected within postprandial 6 h. Within postprandial 2 h, the higher circulating glucose levels induced by HDC intake might inhibit the appetite (decreased orexigenic npy and agrp while increased anorexigenic pomc expressions) through triggering brain glucosensing mechanism (increased central slc2a2 and gck expression). After that, the combined results of unselected slc2a2 and gck expression and elevated tas1r2e-f expression after a HDC diet intake within postprandial 2–6 h suggested that the vegetarian-adapted sweet taste receptors might suppress appetite (further increased anorexigenic cartpt and pomc expressions) through affecting peripheral appetite-regulating peptides in a GCK-independent way. This result raised up the possibility that sweet taste receptors are the potential mediators involved in appetite regulation of herbivorous grass carp in response to HDC intake through peripheral glucosensing system.

Exploring Intestinal Surface Receptors in Oral Nanoinsulin Delivery.

Subcutaneous and inhaled insulins are associated with needle phobia, lipohypertrophy, lipodystrophy, and cough in diabetes treatment. Oral nanoinsulin has been developed, reaping the physiologic benefits of peroral administration. This review profiles intestinal receptors exploitable in targeted delivery of oral nanoinsulin. Intestinal receptor targeting improves oral insulin bioavailability and sustains blood glucose-lowering response. Nonetheless, these studies are conducted in small animal models with no optimization of insulin dose, targeting ligand type and content, and physicochemical and molecular biologic characteristics of nanoparticles against the in vivo/clinical diabetes responses as a function of the intestinal receptor population characteristics with diabetes progression. The interactive effects between nanoinsulin and antidiabetic drugs on intestinal receptors, including their up-/downregulation, are uncertain. Sweet taste receptors upregulate SGLT-1, and both have an undefined role as new intestinal targets of nanoinsulin. Receptor targeting of oral nanoinsulin represents a viable approach that is relatively green, requiring an in-depth development of the relationship between receptors and their pathophysiological profiles with physicochemical attributes of the oral nanoinsulin. SIGNIFICANCE STATEMENT: Intestinal receptor targeting of oral nanoinsulin improves its bioavailability with sustained blood glucose-lowering response. Exploring new intestinal receptor and tailoring the design of oral nanoinsulin to the pathophysiological state of diabetic patients is imperative to raise the insulin performance to a comparable level as the injection products.

Genetic variations in bitter and sweet taste receptors in Taiwanese patients with chronic rhinosinusitis.

Genetic variations of bitter and sweet taste receptors have been related to the pathophysiology of chronic rhinosinusitis (CRS). In this study, we attempted to explore the genetic variations of bitter and sweet taste receptors in Taiwanese CRS patients. Five hundred and sixty-six CRS patients and 5,660 control subjects were selected from participants in the Taiwan Precision Medicine Initiative. Amongst the 566 CRS patients, 186 were with nasal polyps (CRSwNP), while the other 380 were without (CRSsNP). Surgical specimens obtained from 292 CRS patients revealed that 177 were eosinophilic CRS, with the other 115 being non-eosinophilic CRS. There were 591,048 single nucleotide polymorphisms (SNPs) for analysis in all the eligible subjects, including 2 bitter taste receptor SNPs (rs713598, rs10246939) and 1 sweet taste receptor SNP (rs35874116). The minor allele frequencies (MAFs) of rs713598, rs10246939 and rs35874116 were 0.298, 0.297 and 0.078 for CRS patients and 0.306, 0.306 and 0.087 for the control subjects, were 0.301. 0.301 and 0.067 in CRSwNP patients, and 0.295, 0.295 and 0.084 in CRSsNP patients, and were 0.302, 0.302 and 0.085 in the eosinophilic CRS patients, and 0.283,0.287 and 0.087 in the non-eosinophilic CRS patients. The MAFs of rs713598, rs10246939 and rs35874116 were not significantly different between CRS patients and control subjects, between CRSwNP and CRSsNP patients, and between eosinophilic CRS and non-eosinophilic CRS patients. We did not find an association between three variants of the bitter taste receptor TAS2R38 and the sweet taste receptor TAS1R2 and Taiwanese CRS patients. This article is protected by copyright. All rights reserved.

Impact of lactisole on the time-intensity profile of selected sweeteners in dependence of the binding site.

Currently, there is limited insight into the influence of the different binding sites of agonists and antagonists of the sweet taste receptor TAS1R2/TAS1R3 on temporal sensory properties of sweet tasting compounds. We investigated whether the binding site and a competitive or allosteric inhibition of TAS1R2/TAS1R3 influence the time-dependent sensory perception and in vitro TAS1R2/TAS1R3-activation profiles. We compared time-intensity ratings of cyclamate, NHDC, acesulfameK, and aspartame with and without lactisole with the corresponding TAS1R2/TAS1R3-activation in transfected HEK293 cells. In combination with lactisole, cyclamate and NHDC demonstrated a shift of the dose-response curve corresponding to a competitive inhibition by lactisole in the sensory and the cell experiments. Allosteric inhibition by lactisole for aspartame and acesulfame K was seen in the cell experiments, but not the sensory ratings. In conclusion, the data do not support a major impact of the binding site on the time-intensity profile of the tested sweeteners.

Astragalus Polysaccharides Alleviate Type 2 Diabetic Rats by Reversing the Expressions of Sweet Taste Receptors and Genes Related to Glycolipid Metabolism in Liver.

Sweet taste receptors (STRs) play an important role in glucose metabolism, and type 2 diabetic rats have abnormal expressions of STRs in multiple tissues. Astragalus polysaccharides (APS) has shown a significant therapeutic effect on type 2 diabetes mellitus (T2DM), but its mechanism needs to be further clarified. T2DM rat model was induced by intraperitoneal streptozotocin injection and treated with APS for 8 weeks. Daily indicators of experimental rats were observed, and expression levels of STRs and genes related to glycolipid metabolism were determined by real-time quantitative PCR and western blot. The present study revealed that APS alleviated the symptoms of T2DM rats, improved HOMA-IR and promoted insulin secretion. Gene expression analysis found that APS significantly increased the expressions of signaling molecules in STRs pathways, including taste receptor family 1 member 2 (T1R2), α-gustducin (Gα) and transient receptor potential cation channel subfamily member 5 (TRPM5), and reversed the expressions of genes related to glucolipid metabolism, including glucose transporters 2 and 4 (GLUT2 and GLUT4), pyruvate carboxylase (PC), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) in the liver of T2DM rats. However, APS had no influences on the expressions of genes, including glycogen synthase kinase-3 beta (GSK-3β), pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver of T2DM rats. These results suggested that the physiological roles of STRs in the liver were involved with glucose transport and metabolism. APS alleviated T2DM rats by activating the STRs pathway, and promoted glucose transport and lipogenesis.

Functional Characterization of the Venus Flytrap Domain of the Human TAS1R2 Sweet Taste Receptor.

The human sweet taste receptor is a heterodimeric receptor composed of two distinct G-protein-coupled receptors (GPCRs), TAS1R2 and TAS1R3. The TAS1R2 and TAS1R3 subunits are members of a small family of class C GPCRs whose members share the same architecture, comprising a Venus Flytrap (VFT) module linked to the seven transmembrane domains (TMDs) by a short cysteine-rich region (CRR). The VFT module of TAS1R2 contains the primary binding site for most of the sweet-tasting compounds, including natural sugars and artificial and natural sweeteners. However, cellular assays, molecular docking and site-directed mutagenesis studies have revealed that the VFT, CRR and TMD of TAS1R3 interact with some sweeteners, including the sweet-tasting protein brazzein. The aim of this study was to better understand the contribution of TAS1R2-VFT in the binding of sweet stimuli. To achieve this, we heterologously expressed human TAS1R2-VFT (hTAS1R2-VFT) in Escherichia coli. Circular dichroism spectroscopic studies revealed that hTAS1R2-VFT was properly folded with evidence of secondary structures. Using size-exclusion chromatography coupled with light scattering, we found that hTAS1R2-VFT behaves as a monomer. Ligand binding quantified by intrinsic tryptophan fluorescence showed that hTAS1R2-VFT is capable of binding sweet stimuli with Kd values, in agreement with physiological detection. Furthermore, we investigated whether the impact of point mutations, already shown to have deleterious effects on cellular assays, could impact the ability of hTAS1R2-VFT to bind sweet ligands. As expected, the ligand affinities of hTAS1R2-VFT were drastically reduced through the introduction of single amino acid substitutions (D278A and E382A) known to abolish the response of the full-length TAS1R2/TAS1R3 receptor. This study demonstrates the feasibility of producing milligram quantities of hTAS1R2-VFT to further characterize the mechanism of binding interaction and perform structural studies.

Impact of dietary sucralose and sucrose-sweetened water intake on lipid and glucose metabolism in male mice.

Overconsumption of sugar-sweetened beverages (SSBs) is associated with an increased risk of metabolic disorders, including obesity and diabetes. However, accumulating evidence also suggests the potential negative impact of consuming nonnutritive sweeteners (NNSs) on weight and glycaemic control. The metabolic effects of sucralose, the most widely used NNS, remain controversial. This study aimed to compare the impact of intake of dietary sucralose (acceptable daily intake dose, ADI dose) and sucrose-sweetened water (at the same sweetness level) on lipid and glucose metabolism in male mice. Sucralose (0.1mg/mL) or sucrose (60mg/mL) was added to the drinking water of 8-week-old male C57BL/6 mice for 16weeks, followed by oral glucose and intraperitoneal insulin tolerance tests, and measurements of bone mineral density, plasma lipids, and hormones. After the mice were sacrificed, the duodenum and ileum were used for examination of sweet taste receptors (STRs) and glucose transporters. A significant increase in fat mass was observed in the sucrose group of mice after 16weeks of sweetened water drinking. Sucrose consumption also led to increased levels of plasma LDL, insulin, lipid deposition in the liver, and increased glucose intolerance in mice. Compared with the sucrose group, mice consuming sucralose showed much lower fat accumulation, hyperlipidaemia, liver steatosis, and glucose intolerance. In addition, the daily dose of sucralose only had a moderate effect on T1R2/3 in the intestine, without affecting glucose transporters and plasma insulin levels. Compared with mice consuming sucrose-sweetened water, daily drinking of sucralose within the ADI dose had a much lower impact on glucose and lipid homeostasis.

Sweet taste receptor agonists attenuate macrophage IL-1β expression and eosinophilic inflammation linked to autophagy deficiency in myeloid cells.

BackgroundEosinophilic inflammation is a hallmark of refractory chronic rhinosinusitis (CRS) and considered a major therapeutic target. Autophagy deficiency in myeloid cells plays a causal role in eosinophilic CRS (ECRS) via macrophage IL‐1β overproduction, thereby suggesting autophagy regulation as a potential therapeutic modality. Trehalose is a disaccharide sugar with known pro‐autophagy activity and effective in alleviating diverse inflammatory diseases. We sought to investigate the therapeutic potential of autophagy‐enhancing agent, trehalose, or related sugar compounds, and the underlying mechanism focusing on macrophage IL‐1β production in ECRS pathogenesis.MethodsWe investigated the therapeutic effects of trehalose and saccharin on macrophage IL‐1β production and eosinophilia in the mouse model of ECRS with myeloid cell‐specific autophagy‐related gene 7 (Atg7) deletion. The mechanisms underlying their anti‐inflammatory effects were assessed using specific inhibitor, genetic knockdown or knockout, and overexpression of cognate receptors.ResultsUnexpectedly, trehalose significantly attenuated eosinophilia and disease pathogenesis in ECRS mice caused by autophagy deficiency in myeloid cells. This autophagy‐independent effect was associated with reduced macrophage IL‐1β expression. Various sugars recapitulated the anti‐inflammatory effect of trehalose, and saccharin was particularly effective amongst other sugars. The mechanistic study revealed an involvement of sweet taste receptor (STR), especially T1R3, in alleviating macrophage IL‐1β production and eosinophilia in CRS, which was supported by genetic depletion of T1R3 or overexpression of T1R2/T1R3 in macrophages and treatment with the T1R3 antagonist gurmarin.ConclusionOur results revealed a previously unappreciated anti‐inflammatory effect of STR agonists, particularly trehalose and saccharin, and may provide an alternative strategy to autophagy modulation in the ECRS treatment.

Sweet Taste Signaling: The Core Pathways and Regulatory Mechanisms.

Sweet taste, a proxy for sugar-derived calories, is an important driver of food intake, and animals have evolved robust molecular and cellular machinery for sweet taste signaling. The overconsumption of sugar-derived calories is a major driver of obesity and other metabolic diseases. A fine-grained appreciation of the dynamic regulation of sweet taste signaling mechanisms will be required for designing novel noncaloric sweeteners with better hedonic and metabolic profiles and improved consumer acceptance. Sweet taste receptor cells express at least two signaling pathways, one mediated by a heterodimeric G-protein coupled receptor encoded by taste 1 receptor members 2 and 3 (TAS1R2 + TAS1R3) genes and another by glucose transporters and the ATP-gated potassium (KATP) channel. Despite these important discoveries, we do not fully understand the mechanisms regulating sweet taste signaling. We will introduce the core components of the above sweet taste signaling pathways and the rationale for having multiple pathways for detecting sweet tastants. We will then highlight the roles of key regulators of the sweet taste signaling pathways, including downstream signal transduction pathway components expressed in sweet taste receptor cells and hormones and other signaling molecules such as leptin and endocannabinoids.

Artificial sweeteners sucralose and acesulfame potassium: A bittersweet story for the cardiovascular system?

Artificial sweeteners (AS) are well known to activate two categories of receptors; sweet taste receptor with high affinity and bitter taste receptors with low affinity. Interestingly, recent data from our and other groups suggested that these two receptors families are expressed throughout the arterial tree. Therefore, it could be interesting to explore if AS may have an impact on vascular function, and to decipher the role of these taste receptors. The aims of this ongoing work is to investigate whether AS, like sucralose and acesulfame potassium (AceK) (1) exhibit vasomotor effect and (2) in that case determine the underlying mechanisms. Biomolecular and functional investigations have been performed on isolated rodent aortas, human dermal micro-arteries and omental arteries. Ex vivo vasomotor function was assessed using isometric tension measurements in organ bath systems. We first confirmed that both endothelial and smooth muscle cells from rodent and human arteries express the transcripts encoding for TAS1R2 and TAS1R3; the heterodimer receptor known to be responsible for the sweet taste. Our ex vivo data showed that only high concentrations (about 10 mM) of AceK and sucralose induce vasomotor responses. While AceK exhibited a vasoconstrictive effect, sucralose induced vasorelaxation. Both responses were found to be independent of the endothelium. Pharmacological inhibition (gurmarin and lactisol) and the use of a TAS1R3 KO mice model demonstrated that AS vasomotor effects do not rely on the sweet taste receptors. In contrast, inhibition of TAS2Rs abolished all responses suggesting that bitter taste receptors are more likely responsible for the AS-induced vascular effects. Additionally, our last observations show that the vasoconstrictive effect of AceK is mediated by RhoA/ROCK pathway. These evidences support the idea that AS can alter vasomotor signaling in the smooth muscle cells. These acute effects are probably mediated by the bitter taste receptor family. Their activation at the vascular level as well as the underlying pathways remains poorly understood, and the physiopathological consequences need to be further investigated.

Comparison of the Sweet Taste Receptor (TAS1R2) Polymorphism and Nutrient Intakes in Adults

Comparison of the Sweet Taste Receptor (TAS1R2) Polymorphism and Nutrient Intakes in Adults

Impact of sweet, umami, and bitter taste receptor (TAS1R and TAS2R) genomic and expression alterations in solid tumors on survival

Originally identified on the tongue for their chemosensory role, the receptors for sweet, umami, and bitter taste are expressed in some cancers where they regulate important cellular processes including apoptosis and proliferation. We examined DNA mutations (n = 5103), structural variation (n = 7545), and expression (n = 6224) of genes encoding sweet or umami receptors (TAS1Rs) and bitter receptors (TAS2Rs) in 45 solid tumors subtypes compared to corresponding normal tissue using The Cancer Genome Atlas and the Genotype Tissue Expression Project databases. Expression of TAS1R and TAS2R genes differed between normal and cancer tissue, and nonsilent mutations occurred in many solid tumor taste receptor genes (~ 1–7%). Expression levels of certain TAS1Rs/TAS2Rs were associated with survival differences in 12 solid tumor subtypes. Increased TAS1R1 expression was associated with improved survival in lung adenocarcinoma (mean survival difference + 1185 days, p = 0.0191). Increased TAS2R14 expression was associated with worse survival in adrenocortical carcinoma (−1757 days, p < 0.001) and esophageal adenocarcinoma (−640 days, p = 0.0041), but improved survival in non-papillary bladder cancer (+ 343 days, p = 0.0436). Certain taste receptor genes may be associated with important oncologic pathways and could serve as biomarkers for disease outcomes.

Alteration of sweet taste receptor expression in circumvallate papillae of mice with decreased sweet taste preference induced by social defeat stress

Anhedonia is a key diagnostic symptom and central feature of depression symptomatology, but the underlying mechanism remains unknown. In this study, we investigated whether the decrease of sweet taste preference, anhedonia-like behavior in experimental animals, was accompanied by alteration of sweet taste receptor expression in circumvallate papillae (CP) of social defeat stress (SDS)-subjected mice. By subjecting to 10-d SDS, male BALB/c and C57BL/6J mice with decreased sociability in a social interaction test were defined as SDS-susceptible ones, and they exhibited a depressive-like behavior in a forced swim test. In SDS-susceptible BALB/c mice, a two-bottle choice test with a sucrose solution revealed a reduction of sweet taste preference, while expression of sweet taste receptors, T1R2 and T1R3, in their CP was elevated, and the morphology of taste buds and numbers of type II-taste cells were not changed. In CP of SDS-susceptible C57BL/6J mice without a decrease of sweet taste preference, in contrast, there was no alteration of sweet taste receptor expression. Together with the finding that the body weight gain of SDS-susceptible BALB/c mice was apparently less than that of control ones, differing from the case of SDS-susceptible C57BL/6J ones, it is suggested that expression of sweet taste receptors in CP of SDS-susceptible BALB/c mice with decreased sweet taste preference might be upregulated to compensate for the stress-induced increase of energy expenditure.

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA1c in a Human Cohort With Variable Levels of Glucose Homeostasis.

The Ile191Val variant of the TAS1R2 gene of sweet taste receptors causes a partial loss-of-function and is associated with reduced glucose excursions in a healthy lean cohort. However, it is unclear whether this polymorphism contributes to the regulation of glucose homeostasis in metabolically unhealthy individuals. Thus, we used participants with variable glycemic profiles and obesity to assess the effects of the TAS1R2-Ile191Val variant. We found that the Val minor allele carriers had lower HbA1c at all levels of fasting glucose and glucose tolerance. These effects were not due to differences in beta-cell function or insulin sensitivity assessed with a frequently sampled intravenous glucose tolerance test. This study extends our previous findings and provides further evidence that sweet taste receptor function may contribute to glucose regulation in humans.

Current Advances and Future Aspects of Sweetener Synergy: Properties, Evaluation Methods and Molecular Mechanisms

Sweetener synergy is the phenomenon in which certain combinations of sweeteners work more effectively than the theoretical sum of the effects of each components. It provides benefits in reducing sweetener dosages and improving their sweetness. Many mixtures of sweeteners with synergistic effects have been reported up to now. Both artificial high-intensity sweeteners and natural sweeteners are popularly used in sweetener mixtures for synergism, although the former seem to display more potential to exhibit synergy than the latter. Furthermore, several evaluation methods to investigate sweetener synergy have been applied, which could lead to discrepancies in results. Moreover, structurally dissimilar sweeteners could cooperatively bind at the different sites in the sweet taste receptor T1R2/T1R3 to activate the receptor, and their hydration characters/packing characteristics in solvents could affect their interaction with the receptor, providing the preliminary explanations for the molecular basis of sweetener synergy. In this article, we firstly present a systematic review, analysis and comment on the properties, evaluation methods and molecular mechanisms of sweetener synergy. Secondly, challenges of sweetener synergy in both theory and practice and possible strategies to overcome these limitations are comprehensively discussed. Finally, future perspectives for this important performance in human sweet taste perception are proposed.

The Role of D-allulose and Erythritol on the Activity of the Gut Sweet Taste Receptor and Gastrointestinal Satiation Hormone Release in Humans: A Randomized, Controlled Trial

BackgroundGlucose induces the release of gastrointestinal (GI) satiation hormones, such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), in part via the activation of the gut sweet taste receptor (T1R2/T1R3). ObjectivesThe primary objective was to investigate the importance of T1R2/T1R3 for the release of cholecystokinin (CCK), GLP-1, and PYY in response to D-allulose and erythritol by assessing the effect of the T1R2/T1R3 antagonist lactisole on these responses and as secondary objectives to study the effect of the T1R2/T1R3 blockade on gastric emptying, appetite-related sensations, and GI symptoms. MethodsIn this randomized, controlled, double-blind, crossover study, 18 participants (5 men) with a mean ± SD BMI (in kg/m2) of 21.9 ± 1.7 and aged 24 ± 4 y received an intragastric administration of 25 g D-allulose, 50 g erythritol, or tap water, with or without 450 parts per million (ppm) lactisole, respectively, in 6 different sessions. 13C-sodium acetate was added to all solutions to determine gastric emptying. At fixed time intervals, blood and breath samples were collected, and appetite-related sensations and GI symptoms were assessed. Data were analyzed with linear mixed-model analysis. ResultsD-allulose and erythritol induced a significant release of CCK, GLP-1, and PYY compared with tap water (all PHolm < 0.0001, dz >1). Lactisole did not affect the D-allulose– and erythritol-induced release of CCK, GLP-1, and PYY (all PHolm > 0.1). Erythritol significantly delayed gastric emptying, increased fullness, and decreased prospective food consumption compared with tap water (PHolm = 0.0002, dz = –1.05; PHolm = 0.0190, dz = 0.69; and PHolm = 0.0442, dz = –0.62, respectively). ConclusionsD-allulose and erythritol stimulate the secretion of GI satiation hormones in humans. Lactisole had no effect on CCK, GLP-1, and PYY release, indicating that D-allulose– and erythritol-induced GI satiation hormone release is not mediated via T1R2/T1R3 in the gut.