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.

Replication of the Taste of Sugar by Formulation of Noncaloric Sweeteners with Mineral Salt Taste Modulator Compositions.

Noncaloric sweeteners have enabled a reduction of carbohydrate sweeteners in the diet for many years, thus combating obesity, diabetes, and other health disorders. However, many consumers reject noncaloric sweeteners, as they exhibit delays in sweetness onset, objectionable lingering sweet aftertaste, and the absence of sugar-like mouthfeel. We propose that the temporal taste differences between carbohydrate and noncaloric sweeteners result from slowed diffusion of the latter to and from sweetener receptors through the amphipathic mucous hydrogel covering the tongue. Also, we demonstrate that formulation of noncaloric sweeteners with K+/Mg2+/Ca2+ mineral salt blends markedly attenuates lingering sweetness, an effect believed to be due to a composite of osmotic and chelate-mediated compaction of the mucous hydrogel covering the tongue. For example, sweetness linger values (intensity units in % sucrose eq) for rebaudioside A and aspartame are reduced from 5.0 (0.5 SD) to 1.6 (0.4 SD) and from 4.0 (0.7 SD) to 1.2 (0.4 SD), respectively, by formulation with 10 mM KCl/3 mM MgCl2/3 mM CaCl2. Finally, we propose that sugar-like mouthfeel is a consequence of K+/Mg2+/Ca2+ activation of the calcium-sensing receptor present in a subset of taste bud cells. For example, the mouthfeel intensity of a sucrose solution increased from 1.8 (0.6 SD) to 5.1 (0.4 SD).

Natural Sweeteners and Sweetness-Enhancing Compounds Identified in Citrus Using an Efficient Metabolomics-Based Screening Strategy.

With the high demand for a healthy diet, it is necessary and important to explore natural sweeteners used in food that enhance palatability but minimize calories. Citrus is considered a good potential source of noncaloric sweeteners, but to date, only one sweetness modulator has been found in this most common fruit crop. Herein, an efficient strategy based on an in-house database and the untargeted and targeted metabolomics analyses was proposed to screen sweeteners or sweet-enhancing compounds from citrus. Eight sweeteners or sweetness-enhancing compounds were screened out, seven of which were newly identified from the genus Citrus. Surprisingly, we identified naturally occurring oxime V, which previously was only known as a synthetic compound. The contents of five compounds, in 11 citrus cultivars or unreleased selections across two production years, were compared. Successful identification of these natural sweeteners and sweetness-enhancing compounds in citrus fruit indicated the potential to identify the relevant biosynthetic pathways and to breed new citrus cultivars containing these compounds that provided both palatability and lower sugar consumption. This study also demonstrated that the proposed metabolomics-based screening strategy could greatly boost the identification of taste modulators with low contents in natural resources.

Analysis of Caloric and Noncaloric Sweeteners Present in Dairy Products Aimed at the School Market and Their Possible Effects on Health.

Over the past decades, Mexico has become one of the main sweetener-consuming countries in the world. Large amounts of these sweeteners are in dairy products aimed at the children's market in various presentations such as yogurt, flavored milk, flan, and cheeses. Although numerous studies have shown the impact of sweeteners in adults, the current evidence for children is insufficient and discordant to determine if these substances have any risk or benefit on their well-being. Therefore, this study aimed to describe the sweeteners present in 15 dairy products belonging to the school-age children's market in Mexico and their impact on health. These dairy products were selected through a couple of surveys directed at parents of school-age children. After that, the list of ingredients of each product was analyzed to identify their sweetener content. From there, exhaustive bibliographic research on sweeteners and their possible health effects was carried out, which included 109 articles and 18 studies. The results showed that at a neurological, endocrinological, cardiovascular, metabolic, osseous, renal, hepatic, dental, reticular, carcinogenic, and gut microbiota level; sucrose, fructose, high-fructose corn syrup, maltodextrins, sucralose, and acesulfame K, have a negative effect. While maltodextrins, stevia, polydextrose, and modified starch have a positive one. For these reasons, it is necessary to evaluate the advantages and disadvantages that the consumption of each sweetener entails, as well as a determination of the appropriate acceptable daily intake (ADI).

Acute glycemic and insulinemic effects of low-energy sweeteners: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: It has been suggested that low-energy sweeteners (LES) may be associated with an increased risk of metabolic diseases, possibly due to stimulation of glucose-responsive mechanisms. OBJECTIVE: We conducted a systematic review and meta-analysis of human intervention studies examining the acute effect of LES intake on postprandial glucose (PPG) and postprandial insulin (PPI) responses, in order to comprehensively and objectively quantify these relations. METHODS: We systematically searched the Medline, OVID FSTA, and SCOPUS databases until January 2020. Randomized controlled trials comparing acute postprandial effects on PPG and/or PPI after exposure to LES, either alone, with a meal, or with other nutrient-containing preloads to the same intervention without LES were eligible for inclusion. PPG and PPI responses were calculated as mean incremental area under the curve divided by time. Meta-analyses were performed using random effects models with inverse variance weighing. RESULTS: Twenty-six papers (34 PPG trials and 29 PPI trials) were included. There were no reports of statistically significant differences in the effects of LES on PPG and PPI responses compared with control interventions. Pooled effects of LES intake on the mean change difference in PPG and PPI were -0.02 mmol/L (95% CI: -0.09, 0.05) and -2.39 pmol/L (95% CI: -11.83, 7.05), respectively. The results did not appreciably differ by the type or dose of LES consumed, cointervention type, or fasting glucose and insulin levels. Among patients with type 2 diabetes, the mean change difference indicated a smaller PPG response after exposure to LES compared with the control (-0.3 mmol/L; 95% CI: -0.53, -0.07). CONCLUSIONS: Ingestion of LES, administered alone or in combination with a nutrient-containing preload, has no acute effects on the mean change in postprandial glycemic or insulinemic responses compared with a control intervention. Apart from a small beneficial effect on PPG (-0.3 mmol/L) in studies enrolling patients with type 2 diabetes, the effects did not differ by type or dose of LES, or fasting glucose or insulin levels. This review and meta-analysis was registered at PROSPERO as CRD42018099608.

Review of the scientific evidence and technical opinion on noncaloric sweetener consumption in gastrointestinal diseases. / Revisión de la evidencia científica y opinión técnica sobre el consumo de edulcorantes no calóricos en enfermedades gastrointestinales.

The present review of noncaloric sweeteners (NCSs) by the Asociación Mexicana de Gastroenterología was carried out to analyze and answer some of the most frequent questions and concerns about NCS consumption in patients with gastrointestinal disorders, through a thorough review of the medical literature. A group of gastroenterologists and experts on nutrition, toxicology, microbiology, and endocrinology reviewed and analyzed the published literature on the topic. The working group formulated conclusions, based on the scientific evidence published, to give an opinion with respect to NCS ingestion. Current evidence does not confirm the carcinogenic potential of NCSs. However, the studies analyzed showed that saccharin could have a proinflammatory effect and that polyols can cause gastrointestinal symptoms and manifestations, depending on the dose and type of compound. The ingestion of xylitol, erythritol, sucralose, aspartame, acesulfame K, and saccharin could increase the secretion of the gastrointestinal hormones that regulate intestinal motility, and stevia and its derivatives could have a favorable effect on the percentage of liver fat. Caution should be taken in recommending aspartame consumption in patients with chronic liver disease because it reduces the ratio of branched-chain amino acids to aromatic amino acids. In addition, NCS ingestion could modify the composition of the intestinal microbiota, having an effect on gastrointestinal symptoms and manifestations. It is important to continue conducting causality studies on humans to be able to establish recommendations on NSC consumption.

Noncaloric Sweeteners Induce Peripheral Serotonin Secretion via the T1R3-Dependent Pathway in Human Gastric Parietal Tumor Cells (HGT-1).

The role of sweet taste in energy intake and satiety regulation is still controversial. Noncaloric artificial sweeteners (NCSs) are thought to help reduce energy intake, although little is known about their impact on the satiating neurotransmitter serotonin (5-HT). In the gastrointestinal (GI) tract, 5-HT regulates gastric acid secretion and gastric motility, both part of the complex network of mechanisms regulating food intake and satiety. This study demonstrated a stimulating impact compared to controls (100%) on 5-HT release in human gastric tumor cells (HGT-1) by the NCSs cyclamate (50 mM, 157% ± 6.3%), acesulfame potassium (Ace K, 50 mM, 197% ± 8.6%), saccharin (50 mM, 147% ± 6.7%), sucralose (50 mM, 194% ± 11%), and neohesperidin dihydrochalcone (NHDC, 1 mM, 201% ± 13%). Although these effects were not associated with the sweet taste intensity of the NCSs tested, involvement of the sweet receptor subunit T1R3 in the NCS-evoked response was demonstrated by mRNA expression of TAS1R3, co-incubation experiments using the T1R3 receptor antagonist lactisole, and a TAS1R3 siRNA knockdown approach. Analysis of the downstream signaling revealed activation of the cAMP/ERK/Ca2+ cascade. Co-treatment experiments with 10 mM glucose enhanced the 5-HT release induced by cyclamate, Ace K, saccharin, and sucralose, thereby supporting the enhancing effect of glucose on a NCS-mediated response. Overall, the results obtained identify NCSs as potent inducers of 5-HT release via T1R3 in human gastric parietal cells in culture and warrant in vivo studies to demonstrate their efficacy.

Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice.

Diet soda consumption has not been associated with tangible weight loss. Aspartame (ASP) commonly substitutes sugar and one of its breakdown products is phenylalanine (PHE), a known inhibitor of intestinal alkaline phosphatase (IAP), a gut enzyme shown to prevent metabolic syndrome in mice. We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE's inhibition of endogenous IAP. The design of the study was such that for the in vitro model, IAP was added to diet and regular soda, and IAP activity was measured. For the acute model, a closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. For the chronic model, mice were fed chow or high-fat diet (HFD) with/without ASP in the drinking water for 18 weeks. The results were that for the in vitro study, IAP activity was lower (p < 0.05) in solutions containing ASP compared with controls. For the acute model, endogenous IAP activity was reduced by 50% in the ASP group compared with controls (0.2 ± 0.03 vs 0.4 ± 0.24) (p = 0.02). For the chronic model, mice in the HFD + ASP group gained more weight compared with the HFD + water group (48.1 ± 1.6 vs 42.4 ± 3.1, p = 0.0001). Significant difference in glucose intolerance between the HFD ± ASP groups (53 913 ± 4000.58 (mg·min)/dL vs 42 003.75 ± 5331.61 (mg·min)/dL, respectively, p = 0.02). Fasting glucose and serum tumor necrosis factor-alpha levels were significantly higher in the HFD + ASP group (1.23- and 0.87-fold increases, respectively, p = 0.006 and p = 0.01). In conclusion, endogenous IAP's protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of ASP, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks.